Medical implants and fibrosis-inducing agents

ABSTRACT

Implants are used in combination with a fibrosis-inducing agent in order to induce fibrosis that may otherwise not occur when the implant is placed within an animal or increase fibrosis between the implant and the host tissue.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 USC 119(e) of U.S.Provisional Application Ser. No. 60/518,785, filed Nov. 10, 2003; U.S.Provisional Application Ser. No. 60/523,908, filed Nov. 20, 2003; U.S.Provisional Application Ser. No. 60/524,023, filed Nov. 20, 2003; U.S.Provisional Application Ser. No. 60/586,861, filed Jul. 9, 2004; andU.S. Provisional Application Ser. No. 60/578,471, filed Jul. 9, 2004,which applications are incorporated herein by reference. in theirentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to pharmaceutical compositions,methods and devices, and more specifically, to compositions and methodsfor preparing medical implants to make them more adherent to, or, morereadily incorporated within a living tissue. The pharmaceutical agentsand compositions are utilized to create novel drug-coated implants andmedical devices which induce a fibrotic response in the surroundingtissue such that the device is effectively anchored in situ and itsperformance is enhanced.

2. Description of the Related Art

The clinical performance of numerous medical devices depends upon thedevice being effectively anchored into the surrounding tissue to provideeither structural support or to facilitate scarring and healing.Effective attachment of the device into the surrounding tissue, however,is not always readily achieved. One reason for ineffective attachment isthat implantable medical devices generally are composed of materialsthat are highly biocompatible and designed to reduce the host tissueresponse. These materials (e.g., stainless steel, titanium based alloys,fluoropolymers, and ceramics) typically do not provide a good substratefor host tissue attachment and ingrowth during the scarring process. Asa result of poor attachment between the device and the host tissue,devices can have a tendency to migrate within the vessel or tissue inwhich they are implanted. The extent to which a particular type ofmedical device can move or migrate after implantation depends on avariety of factors including the type and design of the device, thematerial(s) from which the device is formed, the mechanical attributes(e.g., flexibility and ability to conform to the surrounding geometry atthe implantation site), the surface properties, and the porosity of thedevice or device surface. The tendency of a device to loosen afterimplantation also depends on the type of tissue and the geometry at thetreatment site, where the ability of the tissue to conform around thedevice generally can help to secure the device in the implantation site.Device migration can result in device failure and, depending on the typeand location of the device, can lead to leakage, vessel occlusion,and/or damage to the surrounding tissue.

Numerous methods and device modifications have been proposed to secureimplantable medical devices in place in the body. In one approach, themedical device is anchored mechanically to biological tissue. Forexample, artificial implants can be anchored to the surrounding tissuesby physical and mechanical means (e.g., screws, cements and poroussurfaces) or by friction. For example, mechanical attachment of a deviceto the site can be effected by using a fastener, such as a suture orstaple. In another approach, the device includes in its designmechanical means for fastening it into the surrounding tissue. Forexample, the device may include metallic spikes, anchors, hooks, barbs,pins, clamps, or a flange or lip to affix the device in place (see,e.g., U.S. Pat. Nos. 4,523,592; 6,309,416; 6,302,905; and 6,152,937). Adisadvantage of mechanical fasteners, however, is that they can damagethe tissue or vessel wall when the device is deployed.

Other methods for preventing device migration have focused onmechanically altering the surface characteristics of the device. Onesuch approach involves scoring or abrading the surface of the implant.The roughened surfaces promote cell, bone or tissue adhesion for betteraffixing of the implants in the body (see, e.g., WO 96/29030A1). Medicaldevices, such as implantable orthopedic devices, may be fixed to hosttissue (e.g., bone) with an adhesive, such as a polymethyl methacrylate(PMMA) bone cement or a bone cement made from calcium phosphates andcalcium aluminate (see, e.g., U.S. Pat. No. 6,723,334). A drawback ofbone cements, however, is that over time the cemented bone-prosthesisinterface can degenerate, and/or the cement itself may weaken and fail,resulting in loosening of the implant.

Chemical or biological modifications of the device surface have beenused to enhance adhesion between an implantable medical device and thesurrounding host tissue. For example, devices have been coated with asubstance to enhance the healing process and/or adhesion of the deviceto the host tissue. In one approach, implantable medical devices havebeen developed which permit infiltration by specific desirable tissuecells. One type of tissue infiltration involves the process known as“endothelialization”, i.e., migration of endothelial cells from adjacenttissue onto or into the device surface. Methods for promotingendothelialization have included applying a porous coating to the devicewhich allows tissue growth into the interstices of the implant surface(see, e.g., WO 96/37165A1). Other efforts at improving host tissueingrowth capability and adhesion of the implant to host tissue includean electrically charged or ionic material (e.g., fluoropolymer) in thetissue-contacting surface of the device (see, e.g., WO 95/19796A1; J. E.Davies, in Surface Characterization of Biomaterials, B. D. Ratner, ed.,pp. 219-234 (1988); and U.S. Pat. No. 5,876,743); biocompatible organicpolymers (e.g., polymers substituted with carbon, sulfur or phosphorousoxyacid groups) to promote osteogenesis at the host-implant interface(see, e.g., U.S. Pat. No. 4,795,475); and coatings made from biologicalmaterials (e.g., collagen) to enhance tissue repair, growth andadaptation at the implant-tissue interface (e.g., U.S. Pat. No.5,002,583).

The above-described approaches, however, have failed to provide asatisfactory long-term solution to the problem of device migration.Thus, there is still a need for an effective, long-lasting andbiocompatible approach for anchoring implantable medical devices into oronto biological tissue.

BRIEF SUMMARY OF THE INVENTION

Briefly stated, the present invention provides compositions for deliveryof selected therapeutic agents via medical implants or implantablemedical devices, as well as methods for making and using these implantsand devices. Within one aspect of the invention, drug-coated ordrug-impregnated implants and medical devices are provided which induceadhesion or fibrosis in the surrounding tissue, or facilitate“anchoring” of the device/implant in situ, thus enhancing the efficacy.Within various embodiments, fibrosis is induced by local or systemicrelease of specific pharmacological agents that become localized to theadjacent tissue.

The repair of tissues following a mechanical or surgical interventioninvolves two distinct processes: (1) regeneration (the replacement ofinjured cells by cells of the same type) and (2) fibrosis (thereplacement of injured cells by connective tissue). There are fourgeneral components to the process of fibrosis (or scarring) including:formation of new blood vessels (angiogenesis), migration andproliferation of fibroblasts, deposition of extracellular matrix (ECM),and remodeling (maturation and organization of the fibrous tissue). Asutilized herein, “induces (promotes) fibrosis” should be understood torefer to agents or compositions which increase or accelerate theformation of fibrous tissue (i.e., by inducing or promoting one or moreof the processes of angiogenesis, fibroblast migration or proliferation,ECM production, and/or remodeling). In addition, numerous therapeuticagents described in this invention can have the additional benefit ofalso promoting tissue regeneration.

Within one embodiment of the invention, an implant or device is adaptedto include or to release an agent that induces fibrosis or regenerationthrough one or more of the mechanisms sited above. Thus, the presentinvention provides devices that comprise a medical implant and at leastone of (i) a fibrosis-inducing agent and (ii) a composition thatcomprises a fibrosis-inducing agent. The agent is present so as toinduce fibrosis formation that may otherwise not occur or increasefibrosis in a statistically significant manner when the implant isplaced within an animal. In another aspect the present invention isdirected to methods wherein both an implant and at least one of (i) afibrosis-inducing agent and (ii) a composition that comprises afibrosis-inducing agent, are placed into an animal, and the agent causesthe formation of fibrosis that may otherwise not occur or increasefibrosis in a statistically significant manner. These and other aspectsof the invention are summarized below.

Thus, in various independent aspects, the present invention provides thefollowing: a device, comprising an orthopedic implant and afibrosis-inducing agent or a composition comprising a fibrosis-inducingagent, wherein the agent induces fibrosis; a device, comprising a maleor female sterilization implant and a fibrosis-inducing agent or acomposition comprising a fibrosis-inducing agent, wherein the agentinduces fibrosis; a device, comprising an implant for treating orpreventing urinary incontinence device and a fibrosis-inducing agent ora composition comprising a fibrosis-inducing agent, wherein the agentinduces fibrosis; a device, comprising an implant for treating orpreventing gastroesophageal reflux disease (GERD) and afibrosis-inducing agent or a composition comprising a fibrosis-inducingagent, wherein the agent induces fibrosis; a device, comprising animplant for treating or preventing obesity and a fibrosis-inducing agentor a composition comprising a fibrosis-inducing agent, wherein the agentinduces fibrosis; a device, comprising an implant for treating orpreventing fecal incontinence device and a fibrosis-inducing agent or acomposition comprising a fibrosis-inducing agent, wherein the agentinduces fibrosis; a device, comprising an embolization implant and afibrosis-inducing agent or a composition comprising a fibrosis-inducingagent, wherein the agent induces fibrosis; a device, comprising a softpalate implant and a fibrosis-inducing agent or a composition comprisinga fibrosis-inducing agent, wherein the agent induces fibrosis; a device,comprising a hernia repair mesh implant and a fibrosis-inducing agent ora composition comprising a fibrosis-inducing agent, wherein the agentinduces fibrosis; and a device, comprising a stent graft and afibrosis-inducing agent or a composition comprising a fibrosis-inducingagent, wherein the agent induces fibrosis. These and other devices aredescribed in more detail herein.

In each of the aforementioned devices, in separate aspects the presentinvention provides that the agent is: an arterial vessel wall irritan;selected from the group consisting of talcum powder, metallic berylliumand oxides thereof, copper, silk, silica, crystalline silicates, talc,quartz dust, and ethanol; a component of extracellular matrix selectedfrom fibronectin, collagen, fibrin, or fibrinogen; a polymer is selectedfrom the group consisting of polylysine, poly(ethylene-co-vinylacetate),chitosan, N-carboxybutylchitosan, and RGD proteins; vinyl chloride or apolymer of vinyl chloride; an adhesive selected from the groupconsisting of cyanoacrylates and crosslinked poly(ethyleneglycol)-methylated collagen; an inflammatory cytokine (e.g., TGFβ, PDGF,VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, andgrowth hormone); connective tissue growth factor (CTGF); a bonemorphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7); leptin, and bleomycin or an analogues or derivative thereof.Optionally, the device may additionally comprise a proliferative agentthat stimulates cellular proliferation. Examples of proliferative agentsinclude: dexamethasone, isotretinoin (13-cis retinoic acid),17-β-estradiol, estradiol, 1-a-25 dihydroxyvitamin D₃,diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid(ATRA), and analogues and derivatives thereof.

In additional aspects, for each of the aforementioned devices combinedwith each of the aforementioned agents, it is, for each combination,independently disclosed that the agent may be present in a compositionalong with a polymer. In one embodiment of this aspect, the polymer isbiodegradable. In another embodiment of this aspect, the polymer isnon-biodegradable. Other features and characteristics of the polymer,which may serve to describe the present invention for every combinationof device and agents described above, are set forth in greater detailherein.

In another aspect, the invention provides a composition, comprising afibrosis-inducing agent and a bulking agent, wherein thefibrosis-inducing agent induces fibrosis. In another aspect, theinvention provides a composition, comprising a fibrosis-inducing agentand a sealant, wherein the agent induces fibrosis. Exemplaryfibrosis-inducing agents include, without limitation: an arterial vesselwall irritant selected from the group consisting of talcum powder,metallic beryllium and oxides thereof, copper, silk, silica, crystallinesilicates, talc, quartz dust, and ethanol; a component of extracellularmatrix selected from fibronectin, collagen, fibrin, or fibrinogen; apolymer selected from polylysine, poly(ethylene-co-vinylacetate),chitosan, N-carboxybutylchitosan, and RGD proteins; vinyl chloride or apolymer of vinyl chloride; an adhesive selected from the groupconsisting of cyanoacrylates and crosslinked poly(ethyleneglycol)-methylated collagen; an inflammatory cytokine (e.g., TGFβ, PDGF,VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1, IL-8, IL-6, and growthhormone); CTGF; BMP (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7);and bleomycin or an analogue or derivative thereof. Optionally, thedevice may additionally comprise an agent that stimulates cellularproliferation. Examples of proliferative agents include: dexamethasone,isotretinoin, 17-β-estradiol, estradiol, diethylstibesterol,cyclosporine A, all-trans retinoic acid (ATRA), and analogues andderivatives thereof. Bulking agents and sealants are described herein.

In addition to devices, the present invention also provides methods. Forexample, in additional aspects of the present invention, for each of theaforementioned devices, and for each of the aforementioned combinationsof the devices with the fibrosis-inducing agents, the present inventionprovides methods whereby a specified device is implanted into an animal,and a specified agent associated with the device induces fibrosis thatmay otherwise not occur or increases fibrosis in a statisticallysignificant manner. Each of the devices identified herein may be a“specified device”, and each of the fibrosis-inducing agents identifiedherein may be a “fibrosis-inducing agent”, where the present inventionprovides, in independent embodiments, for each possible combination ofthe device and the agent.

The agent may be associated with the device prior to the device beingplaced within the animal. For example, the agent (or compositioncomprising the agent) may be coated onto an implant, and the resultingdevice then placed within the animal. In addition, or alternatively, theagent may be independently placed within the animal in the vicinity ofwhere the device is to be, or is being, placed within the animal. Forexample, the agent may be sprayed or otherwise placed onto the tissuethat can be contacting the medical implant or may otherwise undergoscarring. To this end, the present invention provides, in independentaspects: a method for treating or preventing spider veins or varicoseveins, comprising injecting into the vein a composition comprising afibrosis-inducing agent; a method for sterilizing a female patient,comprising injecting into a Fallopian tube a composition comprising afibrosis-inducing agent; a method for treating or preventing urinaryincontinence, comprising injecting into an urethra a compositioncomprising a fibrosis-inducing agent; a method for treating orpreventing GERD, comprising injecting into a lower esophageal sphinctera composition comprising a fibrosis-inducing agent; a method fortreating or preventing fecal incontinence, comprising injecting into ananal sphincter a composition comprising a fibrosis-inducing agent; amethod for treating or preventing snoring or sleep apnea, comprisinginjecting into a soft palate a composition comprising afibrosis-inducing agent; a method for blocking an artery, comprisinginjecting into the artery a composition comprising a fibrosis-inducingagent; a method for sealing an air leak in a lung, comprising sprayingonto the surface of the lung a composition comprising afibrosis-inducing agent; a method for treating or preventingdiverticulitis, comprising delivering into a diverticulum a compositioncomprising a fibrosis-inducing agent; a method for treating orpreventing arthritis, comprising injecting into a damaged joint acomposition comprising a fibrosis-inducing agent; a method for repairinga damaged shoulder capsule, comprising spraying onto an anterior capsulea composition comprising a fibrosis-inducing agent; a method forrepairing a damaged tendon or ligament, comprising spraying onto thetendon or ligament a composition comprising a fibrosis-inducing agent; amethod for treating a damaged spinal disc, comprising injecting into anintervertebral disc space a composition comprising a fibrosis-inducingagent.

In additional aspects, for each of the aforementioned methods used incombination with each of the aforementioned agents, it is, for eachcombination, independently disclosed that the agent may be present in acomposition along with a polymer. In one embodiment of this aspect, thepolymer is biodegradable. In another embodiment of this aspect, thepolymer is non-biodegradable. Other features and characteristics of thepolymer, which may serve to describe the present invention for everycombination of device and agents described above, are set forth ingreater detail herein. In addition to, or in lieu of the polymer, thecomposition may contain collagen.

These and other aspects of the present invention can become evident uponreference to the following detailed description. In addition, variousreferences are set forth herein which describe in more detail certainprocedures and/or compositions (e.g., polymers), and are thereforeincorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the effect of cyclosporine A on proliferationof human smooth muscle cells.

FIG. 2 is a graph showing the effect of dexamethasone on proliferationof human fibroblasts.

FIG. 3 is a graph showing the effect of all-trans retinoic acid (ATRA)on proliferation of human smooth muscle cells.

FIG. 4 is a graph showing the effect of isotretinoin on proliferation ofhuman smooth muscle cells.

FIG. 5 is a graph showing the effect of 17-β-estradiol on proliferationof human fibroblasts.

FIG. 6 is a graph showing the effect of 1a,25-dihydroxy-vitamin D₃ onproliferation of human smooth muscle cells.

FIG. 7 is a graph showing the effect of PDGF-BB on smooth muscle cellmigration.

FIG. 8 is a bar graph showing the area of granulation tissue in carotidarteries exposed to silk coated perivascular polyurethane (PU) filmsrelative to arteries exposed to uncoated PU films.

FIG. 9 is a bar graph showing the area of granulation tissue in carotidarteries exposed to silk suture coated perivascular PU films relative toarteries exposed to uncoated PU films.

FIG. 10 is a bar graph showing the area of granulation tissue in carotidarteries exposed to natural and purified silk powder and wrapped withperivascular PU film relative to a control group in which arteries arewrapped with perivascular PU film only.

FIG. 11 is a bar graph showing the area of granulation tissue (at 1month and 3 months) in carotid arteries sprinkled with talcum powder andwrapped with perivascular PU film relative to a control group in whicharteries are wrapped with perivascular PU film only.

FIG. 12 is a bar graph showing indicating the area of perivasculargranulation tissue quantified by computer-assisted morphometric analysisin rat carotid arteries treated with control uncoated PU films and withPU films treated with degummed and virgin silk strands. As shown in thefigure, both types of silk markedly increased granulation tissue growtharound the blood vessel to the same extent.

FIG. 13 shows representative histology sections of rat carotid arteriestreated with PU films coated with degummed and virgin silk strands. Asshown in the figure, both types of silk induced a marked tissue reactionaround the treated blood vessel. Movat stain, 100×.

FIG. 14 shows representative histology sections of rat carotid arteriestreated with PU films coated with degummed and virgin silk strandsshowing the granulation tissue that has grown around the treatedvessels. The silk strands have broken down into small particlessurrounded by giant cells and macrophages. The granulation tissue ishighly vascularized and contains numerous inflammatory cells andfibroblasts. Extracellular matrix deposition is also extensive. H&Estain 200×.

FIG. 15 shows the release profile for cyclosporine A from a polyurethanefilm as analyzed by HPLC.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses pharmaceutical agents which promote oneor more aspects of the production of fibrous (scar) tissue or tissueregeneration. Furthermore, compositions and methods are described forcoating medical devices and implants with drug-delivery compositionssuch that the pharmaceutical agent is delivered in therapeutic levelsover a period sufficient for fibrosis and healing to occur. The presentinvention also describes various compositions and methods for enhancingthe production of scar tissue adjacent to or on the surface of theimplant are described. Numerous specific implants and devices aredescribed that are capable of producing superior clinical results as aresult of being coated with agents that promote scarring and healing, aswell as other related advantages.

Definitions

Prior to setting forth the invention, it may be helpful to anunderstanding thereof to first set forth definitions of certain termsthat is used hereinafter.

“Medical Device” (or “implant,” or “medical implant,” or implantablemedical device”) refers to any object placed in the body for the purposeof restoring physiological function, reducing/alleviating symptomsassociated with disease, and/or repairing/replacing damaged or diseasedorgans and tissues. While normally composed of biologically compatiblesynthetic materials (e.g., medical-grade stainless steel, titanium andother metals, polymers such as polyurethane, silicon, polylactic acid(PLA), polyglycolic acid (PLGA) and other materials), other materialsthat are exogenous, some medical devices and implants include materialsderived from animals (e.g., “xenografts” such as whole animal organs;animal tissues such as heart valves; naturally occurring orchemically-modified molecules such as collagen, hyaluronic acid,proteins, carbohydrates and others), human donors (e.g., “allografts”such as whole organs; tissues such as bone grafts, skin grafts andothers), or from the patients themselves (e.g., “autografts” such assaphenous vein grafts, skin grafts, tendon/ligament/muscle transplants).Medical devices of particular utility in the present invention include,but are not restricted to, orthopaedic implants (artificial joints,ligaments and tendons, screws, plates, and other implantable hardware),dental implants, intravascular implants (particularly arterial andvenous occlusion devices and implants; vascular destructive implants),male and female contraceptive or sterilization devices and implants,implantable tissue bulking agents for incontinence (esophageal,urethral, anal), soft palate implants, embolization agents, pulmonarysealants, surgical meshes (e.g., hernia repair meshes, tissuescaffolds), fistula treatments, and spinal implants (e.g., artificialintervertebral discs, spinal fusion devices, etc.).

“Fibrosis,” “Scarring,” or “Fibrotic Response” refers to the formationof fibrous tissue in response to injury or medical intervention.Therapeutic agents which promote (also referred to interchangeablyherein as “induce,” “stimulate,” “cause,” and the like) fibrosis orscarring are referred to interchangeably herein as “fibrosis-inducingagents,” “scarring agents,” “fibrosing agents,” “adhesion-inducingagents,” and the like, where these agents do so through one or moremechanisms including: inducing or promoting angiogenesis, stimulatingmigration or proliferation of connective tissue cells (such asfibroblasts, smooth muscle cells, vascular smooth muscle cells),inducing ECM production, and/or promoting tissue remodeling. Inaddition, numerous therapeutic agents described in this invention canhave the additional benefit of also promoting tissue regeneration (thereplacement of injured cells by cells of the same type).

“Sclerosing” refers to a tissue reaction in which an irritant is appliedlocally to a tissue which results in an inflammatory reaction and isfollowed by scar tissue formation at the site of irritation. Apharmaceutical agent that induces or promotes sclerosis is referred toas a “sclerosant,” or a “sclerosing agent.” Representative examples ofsclerosants include ethanol, dimethyl sulfoxide, surfactants (e.g.,Triton X, sorbitan monolaurate, sorbitan sesquioleate, glycerolmonostearate and polyoxyethylene, polyoxyethylene cetyl ether, etc.),sucrose, sodium chloride, dextrose, glycerin, minocycline, tetracycline,doxycycline, polidocanol, sodium tetradecyl sulfate, sodium morrhuate,ethanolamine, phenol, sarapin and sotradecol.

“Release of an agent” refers to any statistically significant presenceof the agent, or a subcomponent thereof, which has disassociated fromthe implant/device.

Any concentration ranges, percentage range, or ratio range recitedherein are to be understood to include concentrations, percentages orratios of any integer within that range and fractions thereof, such asone tenth and one hundredth of an integer, unless otherwise indicated.Also, any number range recited herein relating to any physical feature,such as polymer subunits, size or thickness, are to be understood toinclude any integer within the recited range, unless otherwiseindicated. It should be understood that the terms “a” and “an” as usedabove and elsewhere herein refer to “one or more” of the enumeratedcomponents. As used herein, the term “about” means±15%.

As discussed above, the present invention provides compositions, methodsand devices relating to medical implants, which greatly increase theirability to scar in place and incorporate into the surrounding tissue.Described in more detail below are methods for constructing medicalimplants, compositions and methods for generating medical implants whichpromote fibrosis, and methods for utilizing such medical implants.

A. Medical Implants

Medical implants of the present invention contain and/or are adapted torelease an agent which induces or promotes adhesion between the implantand tissue or a fibrotic reaction. In certain embodiments, the medicalimplant, when placed in to a tissue, releases an agent that induces orpromotes adhesion between the implant and the tissue or a fibroticreaction. In other embodiments, the medical implant contains or is madeof a fibrosing agent, but does not release the fibrosing agent. In suchembodiments, the fibrosing agent contained in the medical implantinduces or promotes fibrosis by direct contact of the agent to thetissue where the implant is placed.

Representative examples of medical implants include: orthopaedicimplants (artificial joints, ligaments and tendons, screws, plates, andother implantable hardware), dental implants, intravascular implants(particularly arterial and venous occlusion devices and implants;vascular destructive implants), male and female contraceptive orsterilization devices and implants, implantable tissue bulking agentsfor incontinence (esophageal, urethral, anal), soft palate implants,embolization agents, pulmonary sealants, surgical meshes (e.g., herniarepair meshes, tissue scaffolds), fistula treatments, and spinalimplants (e.g., artificial intervertebral discs, spinal fusion devices,etc.).

B. Therapeutic Agents

Briefly, numerous therapeutic agents (also referred to herein as‘therapeutic agents’ or ‘drugs’) have been identified that can beutilized within the context of the present invention. The agent may beformulated with one or more other materials, e.g., a polymeric carrier,where formulations are discussed below. Many suitable therapeutic agentsare specifically identified herein, and others may be readily determinedbased upon in vitro and in vivo (animal) models such as those providedin Examples 13-20; 33-34; and 40. Therapeutic agents which promotefibrosis can be identified through in vivo models such as the ratcarotid artery model (Examples 17-20).

In one aspect, the fibrosis or adhesion-inducing agent is silk. Silkrefers to a fibrous protein, and may be obtained from a number ofsources, typically spiders and silkworms. Typical silks contain about75% of actual fiber, referred to as fibroin, and about 35% sericin,which is a gummy protein that holds the filaments together. Silkfilaments are generally very fine and long—as much as 300-900 meterslong. There are several species of domesticated silkworm that are usedin commercial silk production, however, Bombyx mori is the most common,and most silk comes from this source. Other suitable silkworms includePhilosamia cynthia ricini, Antheraea yamamai, Antheraea pernyi, andAntheraea mylitta. Spider silk is relatively more difficult to obtain,however, recombinant techniques hold promise as a means to obtain spidersilk at economical prices (see, e.g., U.S. Pat. Nos. 6,268,169;5,994,099; 5,989,894; and 5,728,810, which are exemplary only).Biotechnology has allowed researchers to develop other sources for silkproduction, including animals (e.g., goats) and vegetables (e.g.,potatoes). Silk from any of these sources may be used in the presentinvention.

A commercially available silk protein is available from Croda, Inc., ofParsippany, N.J., and is sold under the trade names CROSILK LIQUID (silkamino acids), CROSILK 10,000 (hydrolyzed silk), CROSILK POWDER (powderedsilk), and CROSILKQUAT (cocodiammonium hydroxypropyl silk amino acid).Another example of a commercially available silk protein is SERICIN,available from Pentapharm, LTD, a division of Kordia, BV, of theNetherlands. Further details of such silk protein mixtures can be foundin U.S. Pat. No. 4,906,460, to Kim, et al., assigned to Sorenco. Silkuseful in the present invention includes natural (raw) silk, hydrolyzedsilk, and modified silk, i.e., silk that has undergone a chemical,mechanical, or vapor treatment, e.g., acid treatment or acylation (see,e.g., U.S. Pat. No. 5,747,015).

Raw silk is typically twisted into a strand sufficiently strong forweaving or knitting. Four different types of silk thread may be producedby this procedure: organzine, crepe, tram and thrown singles. Organzineis a thread made by giving the raw silk a preliminary twist in onedirection and then twisting two of these threads together in theopposite direction. Crepe is similar to organzine but is twisted to amuch greater extent. Twisting in only one direction two or more raw silkthreads makes tram. Thrown singles are individual raw silk threads thatare twisted in only one direction. Any of these types of silk threadsmay be used in the present invention.

The silk used in the present invention may be in any suitable form thatallows the silk to be joined with the medical implant, e.g., the silkmay be in thread or powder-based forms. The silk can be prepared in thepowdered form by several different methods. For example the silk can bemilled (e.g., cryomill) into a powdered form. Alternatively the silk canbe dissolved in a suitable solvent (e.g., HFIP or 9M LiBr) and thensprayed (electrospray, spray dry) or added to a non-solvent to produce apowder. Furthermore, the silk may have any molecular weight, wherevarious molecular weights are typically obtained by the hydrolysis ofnatural silk, where the extent and harshness of the hydrolysisconditions determines the product molecular weight. For example, thesilk may have an average (number or weight) molecular weight of about200 to 5,000. See, e.g., JP-B-59-29199 (examined Japanese patentpublication) for a description of conditions that may be used tohydrolyze silk.

A discussion of silk may be found in the following documents, which areexemplary only: Hinman, M. B., et al. “Synthetic spider silk: a modularfibre” Trends in Biotechnology, 2000, 18(9) 374-379; Vollrath, F. andKnight, D. P. “Liquid crystalline spinning of spider silk” Nature, 2001,410(6828) 541-548; and Hayashi, C. Y., et al. “Hypotheses that correlatethe sequence, structure, and mechanical properties of spider silkproteins” Int. J. Biol. Macromolecules, 1999, 24(2-3), 265-270; and U.S.Pat. No. 6,427,933.

Other representative examples of fibrosis and adhesion-inducing agentsinclude irritants (e.g., talc, talcum powder, copper, metallic beryllium(or its oxides), wool (e.g., animal wool, wood wolol, and syntheticwool), quartz dust, silica, crystalline silicates), polymers (e.g.,polylysine, polyurethanes, poly(ethylene terephthalate),polytetrafluoroethylene (PTFE), poly(alkylcyanoacrylates), andpoly(ethylene-co-vinylacetate)); vinyl chloride and polymers of vinylchloride; peptides with high lysine content; growth factors andinflammatory cytokines involved in angiogenesis, fibroblast migration,fibroblast proliferation, ECM synthesis and tissue remodeling, such asepidermal growth factor (EGF) family, transforming growth factor-α(TGF-α), transforming growth factor-β (TGF-9-1, TGF-9-2, TGF-9-3,platelet-derived growth factor (PDGF), fibroblast growth factor(acidic—aFGF; and basic—bFGF), fibroblast stimulating factor-1,activins, vascular endothelial growth factor (including VEGF-2, VEGF-3,VEGF-A, VEGF-B, VEGF-C, placental growth factor—PIGF), angiopoietins,insulin-like growth factors (IGF), hepatocyte growth factor (HGF),connective tissue growth factor (CTGF), myeloid colony-stimulatingfactors (CSFs), monocyte chemotactic protein, granulocyte-macrophagecolony-stimulating factors (GM-CSF), granulocyte colony-stimulatingfactor (G-CSF), macrophage colony-stimulating factor (M-CSF),erythropoietin, interleukins (particularly IL-1, IL-8, and IL-6), tumornecrosis factor-α (TNF9), nerve growth factor (NGF), interferon-α,interferon-β, histamine, endothelin-1, angiotensin II, growth hormone(GH), and synthetic peptides, analogues or derivatives of these factorsare also suitable for release from specific implants and devices to bedescribed later. Other examples include CTGF (connective tissue growthfactor); inflammatory microcrystals (e.g., crystalline minerals such ascrystalline silicates); bromocriptine, methylsergide, methotrexate,chitosan, N-carboxybutyl chitosan, carbon tetrachloride, thioacetamide,fibrosin, ethanol, bleomycin, naturally occurring or synthetic peptidescontaining the Arg-Gly-Asp (RGD) sequence, generally at one or bothtermini (see e.g., U.S. Pat. No. 5,997,895), and tissue adhesives, suchas cyanoacrylate and crosslinked poly(ethylene glycol)-methylatedcollagen compositions, such as described below. Other examples offibrosis-inducing agents include bone morphogenic proteins (e.g., BMP-2,BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10,BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Of these, BMP-2,BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7 are of particular utility. Bonemorphogenic proteins are described, for example, in U.S. Pat. Nos.4,877,864; 5,013,649; 5,661,007; 5,688,678; 6,177,406; 6,432,919; and6,534,268 and Wozney, J. M., et al. (1988) Science: 242(4885);1528-1534.

Other representative examples of fibrosis-inducing agents includecrosslinked compositions that comprise amino-functional groups. Forexample, amino-functionalized polyethylene glycol (e.g., 4-armedtetra-amino PEG [10k]) can be reacted with a 4-armed NHS functionalizedPEG (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidylglutarate) under basic buffer conditions. In another example a 4-armedthiol functionalized PEG (e.g., pentaerythritol poly(ethyleneglycol)ether tetra-thiol) can be substituted for the 4-armamino-functionalized PEG such that the amount of amino functional groupsin the final composition can be varied. These reagents can be mixed atthe time of application to provide an in situ forming crosslinkedhydrogel. These reagents could be premixed to produce the crosslinkedmaterial. The material can be made in various forms such as rods, tubes,films, slabs or spheres. The crosslinked material could also be milledto produce a particulate material. These materials can be dried (e.g.,air, vacuum, freeze-dried) and used as a dry powdered material.Alternatively the materials can be hydrated just prior to application.These materials can further comprise one of the fibrosis-inducing agentsdescribed herein.

Other representative examples of fibrosis-inducing agents includecomponents of extracellular matrix (e.g., fibronectin, fibrin,fibrinogen, collagen (e.g., bovine collagen), fibrillar andnon-fibrillar collagen, adhesive glycoproteins, proteoglycans (e.g.,heparin sulfate, chondroitin sulfate, dermatan sulfate), hyaluronan,secreted protein acidic and rich in cysteine (SPARC), thrombospondins,tenacin, and cell adhesion molecules (including integrins, vitronectin,fibronectin, laminin, hyaluronic acid, elastin, bitronectin), proteinsfound in basement membranes, and fibrosin) and inhibitors of matrixmetalloproteinases, such as TIMPs (tissue inhibitors of matrixmetalloproteinases) and synthetic TIMPs, e.g., marimistat, batimistat,doxycycline, tetracycline, minocycline, TROCADE, Ro-1130830, CGS 27023A,and BMS-275291.

Within various embodiments of the invention, a device is coated with afirst composition that promotes fibrosis (and/or restenosis) and asecond composition or compound which acts to have an inhibitory effecton pathological processes in or around the treatment site.Representative examples of agents which can inhibit pathologicalprocesses in the treatment site include, but not limited to, thefollowing classes of compounds: anti-inflammatory agents (e.g.,dexamethasone, cortisone, fludrocortisone, prednisone, prednisolone,6α-methylprednisolone, triamcinolone, and betamethasone); MatrixMetalloproteinase (MMP) inhibitors (e.g., marimistat, batimistat, TIMP'srepresentative examples of which are included in U.S. Pat. Nos.5,665,777; 5,985,911; 6,288,261; 5,952,320; 6,441,189; 6,235,786;6,294,573; 6,294,539; 6,563,002; 6,071,903; 6,358,980; 5,852,213;6,124,502; 6,160,132; 6,197,791; 6,172,057; 6,288,086; 6,342,508;6,228,869; 5,977,408; 5,929,097; 6,498,167; 6,534,491; 6,548,524;5,962,481; 6,197,795; 6,162,814; 6,441,023; 6,444,704; 6,462,073;6,162,821; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980;6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637;6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043;6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577;5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502;5,696,082; 5,700,838; 6,444,639; 6,262,080; 6,486,193; 6,329,550;6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847;5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428;5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022;5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548;6,479,502; 5,696,082; 5,700,838; 5,861,436; 5,691,382; 5,763,621;5,866,717; 5,902,791; 5,962,529; 6,017,889; 6,022,873; 6,022,898;6,103,739; 6,127,427; 6,258,851; 6,310,084; 6,358,987; 5,872,152;5,917,090; 6,124,329; 6,329,373; 6,344,457; 5,698,706; 5,872,146;5,853,623; 6,624,144; 6,462,042; 5,981,491; 5,955,435; 6,090,840;6,114,372; 6,566,384; 5,994,293; 6,063,786; 6,469,020; 6,118,001;6,187,924; 6,310,088; 5,994,312; 6,180,611; 6,110,896; 6,380,253;5,455,262; 5,470,834; 6,147,114; 6,333,324; 6,489,324; 6,362,183;6,372,758; 6,448,250; 6,492,367; 6,380,258; 6,583,299; 5,239,078;5,892,112; 5,773,438; 5,696,147; 6,066,662; 6,600,057; 5,990,158;5,731,293; 6,277,876; 6,521,606; 6,168,807; 6,506,414; 6,620,813;5,684,152; 6,451,791; 6,476,027; 6,013,649; 6,503,892; 6,420,427;6,300,514; 6,403,644; 6,177,466; 6,569,899; 5,594,006; 6,417,229;5,861,510; 6,156,798; 6,387,931; 6,350,907; 6,090,852; 6,458,822;6,509,337; 6,147,061; 6,114,568; 6,118,016; 5,804,593; 5,847,153;5,859,061; 6,194,451; 6,482,827; 6,638,952; 5,677,282; 6,365,630;6,130,254; 6,455,569; 6,057,369; 6,576,628; 6,110,924; 6,472,396;6,548,667; 5,618,844; 6,495,578; 6,627,411; 5,514,716; 5,256,657;5,773,428; 6,037,472; 6,579,890; 5,932,595; 6,013,792; 6,420,415;5,532,265; 5,639,746; 5,672,598; 5,830,915; 6,630,516; 5,324,634;6,277,061; 6,140,099; 6,455,570; 5,595,885; 6,093,398; 6,379,667;5,641,636; 5,698,404; 6,448,058; 6,008,220; 6,265,432; 6,169,103;6,133,304; 6,541,521; 6,624,196; 6,307,089; 6,239,288; 5,756,545;6,020,366; 6,117,869; 6,294,674; 6,037,361; 6,399,612; 6,495,568;6,624,177; 5,948,780; 6,620,835; 6,284,513; 5,977,141; 6,153,612;6,297,247; 6,559,142; 6,555,535; 6,350,885; 5,627,206; 5,665,764;5,958,972; 6,420,408; 6,492,422; 6,340,709; 6,022,948; 6,274,703;6,294,694; 6,531,499; 6,465,508; 6,437,177; 6,376,665; 5,268,384;5,183,900; 5,189,178; 6,511,993; 6,617,354; 6,331,563; 5,962,466;5,861,427; 5,830,869; and 6,087,359), cytokine inhibitors(chlorpromazine, mycophenolic acid, rapamycin, 1α-hydroxy vitamin D₃),IMPDH (inosine monophosplate dehydrogenase) inhibitors (e.g.,mycophenolic acid, ribaviran, aminothiadiazole, thiophenfurin,tiazofurin, viramidine) (Representative examples are included in U.S.Pat. Nos. 5,536,747; 5,807,876; 5,932,600; 6,054,472; 6,128,582;6,344,465; 6,395,763; 6,399,773; 6,420,403; 6,479,628; 6,498,178;6,514,979; 6,518,291; 6,541,496; 6,596,747; 6,617,323; and 6,624,184,U.S. Patent Application Nos. 2002/0040022A1, 2002/0052513A1,2002/0055483A1, 2002/0068346A1, 2002/0111378A1, 2002/0111495A1,2002/0123520A1, 2002/0143176A1, 2002/0147160A1, 2002/0161038A1,2002/0173491A1, 2002/0183315A1, 2002/0193612A1, 2003/0027845A1,2003/0068302A1, 2003/0105073A1, 2003/0130254A1, 2003/0143197A1,2003/0144300A1, 2003/0166201A1, 2003/0181497A1, 2003/0186974A1,2003/0186989A1, and 2003/0195202A1, and PCT Publication Nos. WO00/24725A1, WO 00/25780A1, WO 00/26197A1, WO 00/51615A1, WO 00/56331A1,WO 00/73288A1, WO 01/00622A1, WO 01/66706A1, WO 01/79246A2, WO01/81340A2, WO 01/85952A2, WO 02/16382A1, WO 02/18369A2, WO 02/051814A1,WO 02/057287A2, WO 02/057425A2, WO 02/060875A1, WO 02/060896A1, WO02/060898A1, WO 02/068058A2, WO 03/020298A1, WO 03/037349A1, WO03/039548A1, WO 03/045901A2, WO 03/047512A2, WO 03/053958A1, WO03/055447A2, WO 03/059269A2, WO 03/063573A2, WO 03/087071A1, WO99/001545A1, WO 97/40028A1, WO 97/41211A1, WO 98/40381A1, and WO99/55663A1), p38 MAP kinase inhibitors (MAPK) (e.g., GW-2286, CGP-52411,BIRB-798, SB220025, RO-320-1195, RWJ-67657, RWJ-68354, SCIO-469)(Representative examples are included in U.S. Pat. Nos. 6,300,347;6,316,464; 6,316,466; 6,376,527; 6,444,696; 6,479,507; 6,509,361;6,579,874, and 6,630,485, and U.S. Patent Application Publication Nos.2001/0044538A1, 2002/0013354A1, 2002/0049220A1, 2002/0103245A1,2002/0151491A1, 2002/0156114A1, 2003/0018051A1, 2003/0073832A1,2003/0130257A1, 2003/0130273A1, 2003/0130319A1, 2003/0139388A1,2003/0139462A1, 2003/0149031A1, 2003/0166647A1, and 2003/0181411A1, andPCT Publication Nos. WO 00/63204A2, WO 01/21591A1, WO 01/35959A1, WO01/74811A2, WO 02/18379A2, WO 02/064594A2, WO 02/083622A2, WO02/094842A2, WO 02/096426A1, WO 02/101015A2, WO 02/103000A2, WO03/008413A1, WO 03/016248A2, WO 03/020715A1, WO 03/024899A2, WO03/031431A1, WO 03/040103A1, WO 03/053940A1, WO 03/053941A2, WO03/063799A2, WO 03/079986A2, WO 03/080024A2, WO 03/082287A1, WO97/44467A1, WO 99/01449A1, and WO 99/58523A1), and immunomodulatoryagents (rapamycin, everolimus, ABT-578, azathioprine azithromycin,analogues of rapamycin, tacrolimus and derivatives thereof (e.g., EP0184162B1 and those described in U.S. Pat. No. 6,258,823) and everolimusand derivatives thereof (e.g., U.S. Pat. No. 5,665,772). Furtherrepresentative examples of sirolimus analogues and derivatives includeABT-578 and those found in PCT Publication Nos. WO 97/10502, WO96/41807, WO 96/35423, WO 96/03430, WO 96/00282, WO 95/16691, WO95/15328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO94/21644, WO 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO 93/18043, WO93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737, and WO92/05179 and in U.S. Pat. Nos. 6,342,507; 5,985,890; 5,604,234;5,597,715; 5,583,139; 5,563,172; 5,561,228; 5,561,137; 5,541,193;5,541,189; 5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182;5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901; 5,258,389;5,252,732; 5,247,076; 5,225,403; 5,221,625; 5,210,030; 5,208,241;5,200,411; 5,198,421; 5,147,877; 5,140,018; 5,116,756; 5,109,112;5,093,338; and 5,091,389.

Other examples of drugs that may be included in the compositions anddevices of the invention include tyrosine kinase inhibitors, such asimantinib, ZK-222584, CGP-52411, CGP-53716, NVP-MK980-NX, CP-127374,CP-564959, PD-171026, PD-173956, PD-180970, SU-0879, and SKI-606. Otherexamples of drugs that may be included in the compositions and devicesof the invention include MMP inhibitors such as nimesulide, PKF-241-466,PKF-242-484, CGS-27023A, SAR-943, primomastat, SC-77964, PNU-171829,AG-3433, PNU-142769, SU-5402, and dexlipotam. Other examples of drugsthat may be included in the compositions and devices of the inventioninclude p38 MAP kinase inhibitors such as CGH-2466 and PD-98-59. Otherexamples of of drugs that may be included in the compositions anddevices of the invention include immunosuppressants such as argyrin B,macrocyclic lactone, ADZ-62-826, CCl-779, tilomisole, amcinonide,FK-778, AVE-1726, and MDL-28842. Other examples of cytokine inhibitorsinclude TNF-484A, PD-172084, CP-293121, CP-353164, and PD-168787. Otherexamples of drugs that may be included in the compositions and devicesof the invention include include NFKB inhibitors, such as, AVE-0547,AVE-0545, and IPL-576092. Other examples of drugs that may be includedin the compositions and devices of the invention include include HMGCoAreductase inhibitors, such as, pravestatin, atorvastatin, fluvastatin,dalvastatin, glenvastatin, pitavastatin, CP-83101, U-20685, apoptosisantagonist (e.g., troloxamine, TCH-346(N-methyl-N-propargyl-10-aminomethyl-dibenzo(b,f)oxepin), caspaseinhibitors (e.g., PF-5901 (benzenemethanol,alpha-pentyl-3-(2-quinolinylmethoxy)-), and JNK inhibitor (e.g.,AS-602801).

Within various embodiments of the invention, a device incorporates or iscoated with a composition which promotes fibrosis (and/or restenosis),as well as a composition or compound which acts to stimulate cellularproliferation. Representative examples of agents that stimulate cellularproliferation include, pyruvic acid, naltrexone, leptin, D-glucose,insulin, amlodipine, alginate oligosaccharides, minoxidil,dexamethasone, isotretinoin (13-cis retinoic acid), 17-β-estradiol,estradiol, 1-a-25 dihydroxyvitamin D₃, diethylstibesterol, cyclosporineA, L-NAME (L-NG-nitroarginine methyl ester (hydrochloride)), all-transretinoic acid (ATRA), and analogues and derivatives thereof. Otherexamples of agents that stimulate cellular proliferation include:sphingosine 1-phosphate receptor agonist (e.g., FTY-720(1,3-propanediol, 2-amino-2-(2-(4-octylphenyl)ethyl)-, hydrochloride;immunostimulants, such as Imupedone (methanone,[5-amino-2-(4-methyl-1-piperidinyl)phenyl](4-chlorophenyl)-, DIAPEP227synthetic peptide (Peptor Ltd., Israel)); and nerve growth factoragonist, e.g., NG-012(5H,9H,13H,21H,25H,-dibenzo[k,u][1,5,9,15,19]pentaoxacyclotetracosin-5,9,13,21,25-pentone,7,8,11,12,15,16,23,24,27,28-decahydro-2,4,18,20-tetrahydroxy-11-(hydroxymethyl)-7,15,23,27-tetramethyl-,NG-121, SS-701 (2,2′:6′,2″-terpyridine, 4′-(4-methylphenyl)-,trihydrochloride, AMPAlex (piperidine, 1-(6-quinoxalinylcarbonyl)-, RGH-2716(8-[4,4-bis(4-fluorophenyl)butyl]-3-(1,1-dimethylethyl)-4-methylene-1-oxa-3,8-diaza-spiro[4.5]decan-2-one,and TDN-345 (1-oxa-3,8-diazaspiro[4.5]decan-2-one,8-[4,4-bis(4-fluorophenyl)butyl]-3-(1,1-dimethylethyl)-4-methylene-).

Within various embodiments of the invention, a device incorporates or iscoated on one aspect with a composition which promotes fibrosis (and/orrestenosis), as well as with a composition or compound which preventsrestenosis on another aspect of the device. Representative examples ofagents that inhibit restenosis include paclitaxel, sirolimus,everolimus, vincristine, biolimus, mycophenolic acid, ABT-578,cervistatin, simvastatin, methylprednisolone, dexamethasone,actinomycin-D, angiopeptin, L-arginine, estradiol, 17-β-estradiol,tranilast, methotrexate, batimistat, halofuginone, BCP-671, QP-2,lantrunculin D, cytochalasin A, nitric oxide, and analogues andderivatives thereof.

The medical implant may include a fibrosing agent and an anti-thromboticagent and/or antiplatelet agent, which reduces the likelihood ofthrombotic events upon implantation of a medical implant. Within variousembodiments of the invention, a device is coated on one aspect with acomposition which promotes fibrosis (and/or restenosis), as well asbeing coated with a composition or compound which prevents thrombosis onanother aspect of the device. Representative examples of anti-thromboticand/or antiplatelet agents include heparin, heparin fragments, organicsalts of heparin, heparin complexes (e.g., benzalkonium heparinate,tridodecylammonium heparinate), dextran, sulfonated carbohydrates suchas dextran sulphate, coumadin, coumarin, heparinoid, danaparoid,argatroban chitosan sulfate, chondroitin sulfate, danaparoid, lepirudin,hirudin, AMP, adenosine, 2-chloroadenosine, aspirin, phenylbutazone,indomethacin, meclofenamate, hydrochloroquine, dipyridamole, iloprost,streptokinase, and factor Xa inhibitors, such as DX9065a, magnesium, andtissue plasminogen activator. In one aspect, the anti-thrombotic agentis a modified heparin compound, such as a hydrophobically modifiedheparin or modified hirudin compound (e.g., stearylkonium heparin,benzalkonium heparin, cetylkonium heparin, or trdodecylmethyl ammoniumheparin). Further examples of anti-thrombotic agents includeplasminogen, lys-plasminogen, alpha-2-antiplasmin, urokinase,ticlopidine, clopidogrel, glycoprotein IIb/IIIa inhibitors such asabcixamab, eptifibatide, and tirogiban. Other agents capable ofaffecting the rate of clotting include glycosaminoglycans, danaparoid,4-hydroxycourmarin, warfarin sodium, dicumarol, phenprocoumon,indan-1,3-dione, acenocoumarol, anisindione, and rodenticides includingbromadiolone, brodifacoum, diphenadione, chlorophacinone, and pidnone.The thrombogenicity of a medical implant may be reduced by coating theimplant with a polymeric formulation that has anti-thrombogenicproperties. For example, a medical device may be coated with ahydrophilic polymer gel. The polymer gel can comprise a hydrophilic,biodegradable polymer that is physically removed from the surface of thedevice over time, thus reducing adhesion of platelets to the devicesurface. The gel composition can include a polymer or a blend ofpolymers. Representative examples include alginates, chitosan andchitosan sulfate, hyaluronic acid, dextran sulfate, PLURONIC polymers(e.g., F-127 or F87) and chain extended PLURONIC polymers (BASFCorporation, Mt. Olive, N.J.), various polyester-polyether blockcopolymers of various configurations (e.g., AB, ABA, or BAB, where A isa polyester such as PLA, PGA, PLGA, PCL or the like), examples of whichinclude MePEG-PLA, PLA-PEG-PLA, and the like). In one embodiment, theanti-thrombotic composition can include a crosslinked gel formed from acombination of molecules (e.g., PEG) having two or more terminalelectrophilic groups and two or more nucleophilic groups.

In one aspect, the present invention also provides for the combinationof a medical implant (as well as compositions and methods for makingmedical implants) that includes a fibrosing agent and an anti-infectiveagent, which reduces the likelihood of infections in medical implants.Infection is a common complication of the implantation of foreign bodiessuch as medical devices. Foreign materials provide an ideal site formicro-organisms to attach and colonize. It is also hypothesized thatthere is an impairment of host defenses to infection in themicroenvironment surrounding a foreign material. These factors makemedical implants particularly susceptible to infection and makeeradication of such an infection difficult, if not impossible, in mostcases.

The present invention provides agents (e.g., chemotherapeutic agents)that can be incorporated onto or into, or released from, an implantabledevice, and which have potent antimicrobial activity at extremely lowdoses. A wide variety of anti-infective agents can be utilized incombination with a fibrosing agent according to the invention. Discussedin more detail below are several representative examples ofChemotehrapeutic/anti-infective agents that can be used: (A)anthracyclines (e.g., doxorubicin and mitoxantrone), (B)fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g.,methotrexate), (D) podophylotoxins (e.g., etoposide), (E) camptothecins,(F) hydroxyureas, and (G) platinum complexes (e.g., cisplatin).

(A) Anthracyclines

Anthracyclines have the following general structure, where the R groupsmay be a variety of organic groups:

According to U.S. Pat. No. 5,594,158, suitable R groups are as follows:R₁ is CH₃ or CH₂OH; R₂ is daunosamine or H; R₃ and R₄ are independentlyone of OH, NO₂, NH₂, F, Cl, Br, I, CN, H or groups derived from these;R₅ is hydrogen, hydroxyl, or methoxy; and R₆₋₈ are all hydrogen.Alternatively, R₅ and R₆ are hydrogen and R₇ and R₈ are alkyl orhalogen, or vice versa.

According to U.S. Pat. No. 5,843,903, R₁ may be a conjugated peptide.According to U.S. Pat. No. 4,296,105, R₅ may be an ether linked alkylgroup. According to U.S. Pat. No. 4,215,062, R₅ may be OH or an etherlinked alkyl group. R₁ may also be linked to the anthracycline ring by agroup other than C(O), such as an alkyl or branched alkyl group havingthe C(O) linking moiety at its end, such as —CH₂CH(CH₂—X)C(O)—R₁,wherein X is H or an alkyl group (see, e.g., U.S. Pat. No. 4,215,062).R₂ may alternately be a group linked by the functional group═N—NHC(O)—Y, where Y is a group such as a phenyl or substituted phenylring. Alternately R₃ may have the following structure:

in which R₉ is OH either in or out of the plane of the ring, or is asecond sugar moiety such as R₃. R₁₀ may be H or form a secondary aminewith a group such as an aromatic group, saturated or partially saturated5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S.Pat. No. 5,843,903). Alternately, R₁₀ may be derived from an amino acid,having the structure —C(O)CH(NHR₁₁)(R₁₂), in which R₁₁ is H, or forms aC₃₋₄ membered alkylene with R₁₂. R₁₂ may be H, alkyl, aminoalkyl, amino,hydroxyl, mercapto, phenyl, benzyl or methylthio (see U.S. Pat. No.4,296,105).

Exemplary anthracyclines are doxorubicin, daunorubicin, idarubicin,epirubicin, pirarubicin, zorubicin, and carubicin. Suitable compoundshave the structures:

R₁ R₂ R₃ Doxorubicin: OCH₃ C(O)CH₂OH OH out of ring plane Epirubicin:OCH₃ C(O)CH₂OH OH in ring plane (4′ epimer of doxorubicin) Daunorubicin:OCH₃ C(O)CH₃ OH out of ring plane Idarubicin: H C(O)CH₃ OH out of ringplane Pirarubicin: OCH₃ C(O)CH₂OH

Zorubicin: OCH₃ C(CH₃)(═N)NHC(O)C₆H₅ OH Carubicin: OH C(O)CH₃ OH out ofring plane

Other suitable anthracyclines are anthramycin, mitoxantrone, menogaril,nogalamycin, aclacinomycin A, olivomycin A, chromomycin A₃, andplicamycin having the structures:

R₁ R₂ R₃ Menogaril H OCH₃ H Nogalamycin O-sugar H COOCH₃

Ho R₁ R₂ R₃ R₄ Olivomycin A COCH(CH₃)₂ CH₃ COCH₃ H Chromomycin A₃ COCH₃CH₃ COCH₃ CH₃ Plicamycin H H H CH₃

Other representative anthracyclines include, FCE 23762, a doxorubicinderivative (Quaglia et al., J. Liq. Chromatogr. 17(18): 3911-3923,1994), annamycin (Zou et al., J. Pharm. Sci. 82(11): 1151-1154, 1993),ruboxyl (Rapoport et al., J. Controlled Release 58(2): 153-162, 1999),anthracycline disaccharide doxorubicin analogue (Pratesi et al., Clin.Cancer Res. 4(11): 2833-2839, 1998), N-(trifluoroacetyl)doxorubicin and4′-O-acetyl-N-(trifluoroacetyl)doxorubicin (Berube & Lepage, Synth.Commun. 28(6): 1109-1116, 1998), 2-pyrrolinodoxorubicin (Nagy et al.,Proc. Natl. Acad. Sci. U.S.A. 95(4): 1794-1799, 1998), disaccharidedoxorubicin analogues (Arcamone et al., J. Nat'l Cancer lnst 89(16):1217-1223, 1997),4-demethoxy-7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-hexopyranosyl)-α-L-lyxo-hexopyranosyl]adriamicinonedoxorubicin disaccharide analogue (Monteagudo et al., Carbohydr. Res.300(1): 11-16, 1997), 2-pyrrolinodoxorubicin (Nagy et al., Proc.Nat'lAcad. Sci. U.S.A. 94(2): 652-656, 1997), morpholinyl doxorubicinanalogues (Duran et al., Cancer Chemother. Pharmacol. 38(3): 210-216,1996), enaminomalonyl-β-alanine doxorubicin derivatives (Seitz et al.,Tetrahedron Lett. 36(9): 1413-16, 1995), cephalosporin doxorubicinderivatives (Vrudhula et al., J. Med. Chem. 38(8): 1380-5, 1995),hydroxyrubicin (Solary et al., Int. J. Cancer 58(1): 85-94, 1994),methoxymorpholino doxorubicin derivative (Kuhl et al., Cancer Chemother.Pharmacol. 33(1): 10-16, 1993), (6-maleimidocaproyl)hydrazonedoxorubicin derivative (Willner et al., Bioconjugate Chem. 4(6): 521-7,1993), N-(5,5-diacetoxypent-1-yl) doxorubicin (Cherif & Farquhar, J.Med. Chem. 35(17): 3208-14, 1992), FCE 23762 methoxymorpholinyldoxorubicin derivative (Ripamonti et al., Br. J. Cancer 65(5): 703-7,1992), N-hydroxysuccinimide ester doxorubicin derivatives (Demant etal., Biochim. Biophys. Acta 1118(1): 83-90, 1991), polydeoxynucleotidedoxorubicin derivatives (Ruggiero et al., Biochim. Biophys. Acta1129(3): 294-302, 1991), morpholinyl doxorubicin derivatives (EPA434960), mitoxantrone doxorubicin analogue (Krapcho et al., J. Med.Chem. 34(8): 2373-80. 1991), AD198 doxorubicin analogue (Traganos etal., Cancer Res. 51(14): 3682-9, 1991),4-demethoxy-3′-N-trifluoroacetyidoxorubicin (Horton et al., Drug Des.Delivery 6(2): 123-9, 1990), 4′-epidoxorubicin (Drzewoski et al., Pol.J. Pharmacol. Pharm. 40(2): 159-65, 1988; Weenen et al., Eur. J. CancerClin. Oncol. 20(7): 919-26, 1984), alkylating cyanomorpholinodoxorubicin derivative (Scudder et al., J. Nat'l Cancer Inst 80(16):1294-8, 1988), deoxydihydroiodooxorubicin (EPA 275966), adriblastin(Kalishevskaya et al., Vestn. Mosk. Univ., 16(Biol. 1): 21-7, 1988),4′-deoxydoxorubicin (Schoeizel et al., Leuk. Res. 10(12): 1455-9, 1986),4-demethyoxy-4′—O— methyldoxorubicin (Giuliani et al., Proc. Int. Congr.Chemother. 16: 285-70-285-77, 1983), 3′-deamino-3′-hydroxydoxorubicin(Horton et al., J. Antibiot 37(8): 853-8, 1984), 4-demethyoxydoxorubicin analogues (Barbieri et al., Drugs Exp. Clin. Res. 10(2):85-90, 1984), N-L-leucyl doxorubicin derivatives (Trouet et al.,Anthracyclines (Proc. Int. Symp. Tumor Pharmacother.), 179-81, 1983),3′-deamino-3′-(4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S.Pat. No. 4,314,054), 3′-deamino-3′-(4-mortholinyl) doxorubicinderivatives (U.S. Pat. No. 4,301,277), 4′-deoxydoxorubicin and4′-o-methyldoxorubicin (Giuliani et al., Int. J. Cancer 27(1): 5-13,1981), aglycone doxorubicin derivatives (Chan & Watson, J. Pharm. Sci.67(12): 1748-52, 1978), SM 5887 (Pharma Japan 1468: 20, 1995), MX-2(Pharma Japan 1420: 19, 1994), 4′-deoxy-13(S)-dihydro-4′-iododoxorubicin(EP 275966), morpholinyl doxorubicin derivatives (EPA 434960),3′-deamino-3′-(4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S.Pat. No. 4,314,054), doxorubicin-14-valerate, morpholinodoxorubicin(U.S. Pat. No. 5,004,606), 3′-deamino-3′-(3″-cyano-4″-morpholinyldoxorubicin;3′-deamino-3′-(3″-cyano-4″-morpholinyl)-13-dihydoxorubicin);(3′-deamino-3′-(3″-cyano-4″-morpholinyl) daunorubicin;3′-deamino-3′-(3″-cyano-4″-morpholinyl)-3-dihydrodaunorubicin; and3′-deamino-3′-(4″-morpholinyl-5-iminodoxorubicin and derivatives (U.S.Pat. No. 4,585,859), 3′-deamino-3′-(4-methoxy-1-piperidinyl) doxorubicinderivatives (U.S. Pat. No. 4,314,054) and 3-deamino-3-(4-morpholinyl)doxorubicin derivatives (U.S. Pat. No. 4,301,277).

(B) Fluoropyrimidine Analogues

In another aspect, the therapeutic agent is a fluoropyrimidine analog,such as 5-fluorouracil, or an analogue or derivative thereof, includingcarmofur, doxifluridine, emitefur, tegafur, and floxuridine. Exemplarycompounds have the structures: A

R₁ R₂ 5-Fluorouracil H H Carmofur C(O)NH(CH₂)₅CH₃ H Doxifluridine A₁ HFloxuridine A₂ H Emitefur CH₂OCH₂CH₃ B Tegafur C H B

C

Other suitable fluoropyrimidine analogues include 5-FudR(5-fluoro-deoxyuridine), or an analogue or derivative thereof, including5-iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), fluorouridinetriphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP).Exemplary compounds have the structures:

5-Fluoro-2′-deoxyuridine: R = F 5-Bromo-2′-deoxyuridine: R = Br5-Iodo-2′-deoxyuridine: R = I

Other representative examples of fluoropyrimidine analogues includeN3-alkylated analogues of 5-fluorouracil (Kozai et al., J. Chem. Soc.,Perkin Trans. 1(19): 3145-3146, 1998), 5-fluorouracil derivatives with1,4-oxaheteroepane moieties (Gomez et al., Tetrahedron 54(43):13295-13312, 1998), 5-fluorouracil and nucleoside analogues (Li,Anticancer Res. 17-(1A): 21-27, 1997), cis- andtrans-5-fluoro-5,6-dihydro-6-alkoxyuracil (Van der Wilt et al., Br. J.Cancer 68(4): 702-7, 1993), cyclopentane 5-fluorouracil analogues(Hronowski & Szarek, Can. J. Chem. 70(4): 1162-9, 1992),A-OT-fluorouracil (Zhang et al., Zongguo Yiyao Gongye Zazhi 20(11):513-15, 1989), N4-trimethoxybenzoyl-5′-deoxy-5-fluorocytidine and5′-deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Bull. 38(4):998-1003, 1990), 1-hexylcarbamoyl-5-fluorouracil (Hoshi et al., J.Pharmacobio-Dun. 3(9): 478-81, 1980; Maehara et al., Chemotherapy(Basel) 34(6): 484-9, 1988), B-3839 (Prajda et al., In Vivo 2(2): 151-4,1988), uracil-1-(2-tetrahydrofuryl)-5-fluorouracil (Anai et al.,Oncology 45(3): 144-7, 1988),1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-fluorouracil (Suzuko etal., Mol. Pharmacol. 31(3): 301-6, 1987), doxifluridine (Matuura et al.,Oyo Yakuri 29(5): 803-31, 1985), 5′-deoxy-5-fluorouridine (Bollag &Hartmann, Eur. J. Cancer 16(4): 427-32, 1980),1-acetyl-3-O-toluyl-5-fluorouracil (Okada, Hiroshima J. Med. Sci. 28(1):49-66, 1979), 5-fluorouracil-m-formylbenzene-sulfonate (JP 55059173),N′-(2-furanidyl)-5-fluorouracil (JP 53149985) and1-(2-tetrahydrofuryl)-5-fluorouracil (JP 52089680).

These compounds are believed to function as therapeutic agents byserving as antimetabolites of pyrimidine.

(C) Folic Acid Antagonists

In another aspect, the therapeutic agent is a folic acid antagonist,such as methotrexate or derivatives or analogues thereof, includingedatrexate, trimetrexate, raltitrexed, piritrexim, denopterin, tomudex,and pteropterin. Methotrexate analogues have the following generalstructure:

The identity of the R group may be selected from organic groups,particularly those groups set forth in U.S. Pat. Nos. 5,166,149 and5,382,582. For example, R₁ may be N, R₂ may be N or C(CH₃), R₃ and R₃′may H or alkyl, e.g., CH₃, R₄ may be a single bond or NR, where R is Hor alkyl group. R₅, R₆, and/or R₈ may be H, OCH₃, or alternately theycan be halogens or hydro groups. R₇ is a side chain of the generalstructure:

wherein n=1 for methotrexate, n=3 for pteropterin. The carboxyl groupsin the side chain may be esterified or form a salt such as a Zn²⁺ salt.R₉ and R₁₀ can be NH₂ or may be alkyl substituted.

Exemplary folic acid antagonist compounds have the structures:

R₀ R₁ R₂ R₃ R₄ R₅ R₆ R₇ R₈ Methotrexate NH₂ N N H N(CH₃) H H A(n = 1) HEdatrexate NH₂ N N H CH(CH₂CH₃) H H A(n = 1) H Trimetrexate NH₂ CHC(CH₃) H NH H OCH₃ OCH₃ OCH₃ Pteropterin OH N N H NH H H A(n = 3) HDenopterin OH N N CH₃ N(CH₃) H H A(n = 1) H Peritrexim NH₂ N C(CH₃) Hsingle bond OCH₃ H H OCH₃ A:

Other representative examples include 6-S-aminoacyloxymethylmercaptopurine derivatives (Harada et al., Chem. Pharm. Bull. 43(10):793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al., Biol. Pharm.Bull. 18(11): 1492-7, 1995),7,8-polymethyleneimidazo-1,3,2-diazaphosphorines (Nilov et al.,Mendeleev Commun. 2: 67, 1995), azathioprine (Chifotides et al., J.Inorg. Biochem. 56(4): 249-64, 1994), methyl-D-glucopyranosidemercaptopurine derivatives (Da Silva et al., Eur. J. Med. Chem. 29(2):149-52, 1994) and s-alkynyl mercaptopurine derivatives (Ratsino et al.,Khim.-Farm. Zh. 15(8): 65-7, 1981); indoline ring and a modifiedornithine orglutamic acid-bearing methotrexate derivatives (Matsuoka etal., Chem. Pharm. Bull. 45(7): 1146-1150, 1997), alkyl-substitutedbenzene ring C bearing methotrexate derivatives (Matsuoka et al., Chem.Pharm. Bull. 44(12): 2287-2293, 1996), benzoxazine or benzothiazinemoiety-bearing methotrexate derivatives (Matsuoka et al., J. Med. Chem.40(1): 105-111, 1997), 10-deazaminopterin analogues (DeGraw et al., J.Med. Chem. 40(3): 370-376, 1997), 5-deazaminopterin and5,10-dideazaminopterin methotrexate analogues (Piper et al., J. Med.Chem. 40(3): 377-384, 1997), indoline moiety-bearing methotrexatederivatives (Matsuoka et al., Chem. Pharm. Bull. 44(7): 1332-1337,1996), lipophilic amide methotrexate derivatives (Pignatello et al.,World Meet. Pharm. Biopharm. Pharm. Technol., 563-4, 1995),L-threo-(2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamicacid-containing methotrexate analogues (Hart et al., J. Med. Chem.39(1): 56-65, 1996), methotrexate tetrahydroquinazoline analogue(Gangjee, et al, J. Heterocycl. Chem. 32(1): 243-8, 1995),N-(α-aminoacyl)methotrexate derivatives (Cheung et al., Pteridines3(1-2): 101-2, 1992), biotin methotrexate derivatives (Fan et al.,Pteridines 3(1-2): 131-2, 1992), D-glutamic acid or D-erythrou,threo-4-fluoroglutamic acid methotrexate analogues (McGuire et al.,Biochem. Pharmacol. 42(12): 2400-3, 1991), β,γ-methano methotrexateanalogues (Rosowsky et al., Pteridines 2(3): 133-9, 1991),10-deazaminopterin (10-EDAM) analogue (Braakhuis et al., Chem. Biol.Pteridines, Proc. Int Symp. Pteridines Folic Acid Deriv., 1027-30,1989), γ-tetrazole methotrexate analogue (Kalman et al., Chem. Biol.Pteridines, Proc. Int Symp. Pteridines Folic Acid Deriv., 1154-7, 1989),N-(L-α-aminoacyl)methotrexate derivatives (Cheung et al., Heterocycles28(2): 751-8, 1989), meta and ortho isomers of aminopterin (Rosowsky etal., J. Med. Chem. 32(12): 2582, 1989), hydroxymethylmethotrexate (DE267495), γ-fluoromethotrexate (McGuire et al., Cancer Res. 49(16):4517-25, 1989), polyglutamyl methotrexate derivatives (Kumar et al.,Cancer Res. 46(10): 5020-3, 1986), gem-diphosphonate methotrexateanalogues (WO 88/06158), α- and γ-substituted methotrexate analogues(Tsushima et al., Tetrahedron 44(17): 5375-87, 1988), 5-methyl-5-deazamethotrexate analogues (U.S. Pat. No. 4,725,687),Nδ-acyl-Na-(4-amino-4-deoxypteroyl)-L-ornithine derivatives (Rosowsky etal., J. Med. Chem. 31(7): 1332-7, 1988), 8-deaza methotrexate analogues(Kuehl et al., Cancer Res. 48(6): 1481-8, 1988), acivicin methotrexateanalogue (Rosowsky et al., J. Med. Chem. 30(8): 1463-9, 1987), polymericplatinol methotrexate derivative (Carraher et al., Polym. Sci. Technol.(Plenum), 35(Adv. Biomed. Polym.): 311-24, 1987),methotrexate-γ-dimyristoylphophatidylethanolamine (Kinsky et al.,Biochim. Biophys. Acta 917(2): 211-18, 1987), methotrexate polyglutamateanalogues (Rosowsky et al., Chem. Biol. Pteridines, Pteridines FolicAcid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol.Clin. Aspects: 985-8, 1986), poly-γ-glutamyl methotrexate derivatives(Kisliuk et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv.,Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin.Aspects: 989-92, 1986), deoxyuridylate methotrexate derivatives (Webberet al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int.Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects: 659-62,1986), iodoacetyl lysine methotrexate analogue (Delcamp et al., Chem.Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp.Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects: 807-9, 1986),2,.omega.-diaminoalkanoid acid-containing methotrexate analogues(McGuire et al., Biochem. Pharmacol. 35(15): 2607-13, 1986),polyglutamate methotrexate derivatives (Kamen & Winick, Methods Enzymol.122 (Vitam. Coenzymes, Pt. G): 339-46, 1986), 5-methyl-5-deaza analogues(Piper et al., J. Med. Chem. 29(6): 1080-7, 1986), quinazolinemethotrexate analogue (Mastropaolo et al., J. Med. Chem. 29(1): 155-8,1986), pyrazine methotrexate analogue (Lever & Vestal, J. Heterocycl.Chem. 22(1): 5-6, 1985), cysteic acid and homocysteic acid methotrexateanalogues (U.S. Pat. No. 4,490,529), γ-tert-butyl methotrexate esters(Rosowsky et al., J. Med. Chem. 28(5): 660-7, 1985), fluorinatedmethotrexate analogues (Tsushima et al., Heterocycles 23(1): 45-9,1985), folate methotrexate analogue (Trombe, J. Bacteriol 160(3):849-53, 1984), phosphonoglutamic acid analogues (Sturtz & Guillamot,Eur. J. Med. Chem.—Chim. Ther. 19(3): 267-73, 1984),poly(L-lysine)methotrexate conjugates (Rosowsky et al., J. Med. Chem.27(7): 888-93, 1984), dilysine and trilysine methotrexate derivates(Forsch & Rosowsky, J. Org. Chem. 49(7): 1305-9, 1984),7-hydroxymethotrexate (Fabre et al., Cancer Res. 43(10): 4648-52, 1983),poly-γ-glutamyl methotrexate analogues (Piper & Montgomery, Adv. Exp.Med. Biol., 163 (Folyl Antifolyl Polyglutamates): 95-100, 1983),3′,5′-dichloromethotrexate (Rosowsky & Yu, J. Med. Chem. 26(10):1448-52, 1983), diazoketone and chloromethylketone methotrexateanalogues (Gangjee et al., J. Pharm. Sci. 71(6): 717-19, 1982),10-propargylaminopterin and alkyl methotrexate homologs (Piper et al.,J. Med. Chem. 25(7): 877-80, 1982), lectin derivatives of methotrexate(Lin et al., JNCI 66(3): 523-8, 1981), polyglutamate methotrexatederivatives (Galivan, Mol. Pharmacol. 17(1): 105-10, 1980), halogentatedmethotrexate derivatives (Fox, JNCI 58(4): J955-8, 1977),8-alkyl-7,8-dihydro analogues (Chaykovsky et al., J. Med. Chem. 20(10):J1323-7, 1977), 7-methyl methotrexate derivatives anddichloromethotrexate (Rosowsky & Chen, J. Med. Chem. 17(12): J1308-11,1974), lipophilic methotrexate derivatives and3′,5′-dichloromethotrexate (Rosowsky, J. Med. Chem. 16(10): J1190-3,1973), deaza amethopterin analogues (Montgomery et al., Ann. N.Y. Acad.Sci. 186: J227-34, 1971), MX068 (Pharma Japan, 1658: 18, 1999) andcysteic acid and homocysteic acid methotrexate analogues (EPA 0142220);

These compounds are believed to act as antimetabolites of folic acid.

(D) Podophyllotoxins

In another aspect, the therapeutic agent is a Podophyllotoxin, or aderivative or an analogue thereof. Exemplary compounds of this type areetoposide or teniposide, which have the following structures:

Other representative examples of podophyllotoxins include Cu(II)-VP-16(etoposide) complex (Tawa et al., Bioorg. Med. Chem. 6(7): 1003-1008,1998), pyrrolecarboxamidino-bearing etoposide analogues (Ji et al.,Bioorg. Med. Chem. Lett. 7(5): 607-612, 1997), 4β-amino etoposideanalogues (Hu, University of North Carolina Dissertation, 1992),γ-lactone ring-modified arylamino etoposide analogues (Zhou et al., J.Med. Chem. 37(2): 287-92, 1994), N-glucosyl etoposide analogue (Alleviet al., Tetrahedron Lett. 34(45): 7313-16, 1993), etoposide A-ringanalogues (Kadow et al., Bioorg. Med. Chem. Leff. 2(1): 17-22, 1992),4′-deshydroxy-4′-methyl etoposide (Saulnier et al., Bioorg. Med. Chem.Lett. 2(10): 1213-18, 1992), pendulum ring etoposide analogues (Sinha etal., Eur. J. Cancer 26(5): 590-3, 1990) and E-ring desoxy etoposideanalogues (Saulnier et al., J. Med. Chem. 32(7): 1418-20, 1989).

These compounds are believed to act as topoisomerase 11 inhibitorsand/or DNA cleaving agents.

(E) Camptothecins

In another aspect, the therapeutic agent is camptothecin, or an analogueor derivative thereof. Camptothecins have the following generalstructure.

In this structure, X is typically 0, but can be other groups, e.g., NHin the case of 21-lactam derivatives. R₁ is typically H or OH, but maybe other groups, e.g., a terminally hydroxylated C₁₋₃ alkane. R₂ istypically H or an amino containing group such as (CH₃)₂NHCH₂, but may beother groups e.g., NO₂, NH₂, halogen (as disclosed in, e.g., U.S. Pat.No. 5,552,156) or a short alkane containing these groups. R₃ istypically H or a short alkyl such as C₂H₅. R₄ is typically H but may beother groups, e.g., a methylenedioxy group with R₁.

Exemplary camptothecin compounds include topotecan, irinotecan (CPT-11),9-aminocamptothecin, 21-lactam-20(S)-camptothecin,10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin,10-hydroxycamptothecin. Exemplary compounds have the structures:

R₁ R₂ R₃ Camptothecin: H H H Topotecan: OH (CH₃)₂NHCH₂ H SN-38: OH HC₂H₅X: O for most analogs, NH for 21-lactam analogs

Camptothecins have the five rings shown here. The ring labeled E must beintact (the lactone rather than carboxylate form) for maximum activityand minimum toxicity.

Camptothecins are believed to function as topoisomerase I inhibitorsand/or DNA cleavage agents.

(F) Hydroxyureas

The therapeutic agent of the present invention may be a hydroxyurea.Hydroxyureas have the following general structure:

Suitable hydroxyureas are disclosed in, for example, U.S. Pat. No.6,080,874, wherein R₁ is:

and R₂ is an alkyl group having 1-4 carbons and R₃ is one of H, acyl,methyl, ethyl, and mixtures thereof, such as a methylether.

Other suitable hydroxyureas are disclosed in, e.g., U.S. Pat. No.5,665,768, wherein R₁ is a cycloalkenyl group, for exampleN-[3-[5-(4-fluorophenylthio)-furyl]-2-cyclopenten-1-yl]N-hydroxyurea; R₂is H or an alkyl group having 1 to 4 carbons and R₃ is H; X is H or acation.

Other suitable hydroxyureas are disclosed in, e.g., U.S. Pat. No.4,299,778, wherein R₁ is a phenyl group substituted with one or morefluorine atoms; R₂ is a cyclopropyl group; and R₃ and X is H.

Other suitable hydroxyureas are disclosed in, e.g., U.S. Pat. No.5,066,658, wherein R₂ and R₃ together with the adjacent nitrogen form:

wherein m is 1 or 2, n is 0-2 and Y is an alkyl group.

In one aspect, the hydroxyurea has the structure:

These compounds are thought to function by inhibiting DNA synthesis.

(G) Platinum Complexes

In another aspect, the therapeutic agent is a platinum compound. Ingeneral, suitable platinum complexes may be of Pt(II) or Pt(IV) and havethis basic structure:

wherein X and Y are anionic leaving groups such as sulfate, phosphate,carboxylate, and halogen; R₁ and R₂ are alkyl, amine, amino alkyl may befurther substituted, and are basically inert or bridging groups. ForPt(II) complexes Z₁ and Z₂ are non-existent. For Pt(IV) Z₁ and Z₂ may beanionic groups such as halogen, hydroxy, carboxylate, ester, sulfate orphosphate. See, e.g., U.S. Pat. Nos. 4,588,831 and 4,250,189.

Suitable platinum complexes may contain multiple Pt atoms. See, e.g.,U.S. Pat. Nos. 5,409,915 and 5,380,897. For example bisplatinum andtriplatinum complexes of the type:

Exemplary platinum compounds are cisplatin, carboplatin, oxaliplatin,and miboplatin having the structures:

Other representative platinum compounds include (CPA)₂Pt[DOLYM] and(DACH)Pt[DOLYM] cisplatin (Choi et al., Arch. Pharmacal Res. 22(2):151-156, 1999),Cis-[PtCl₂(4,7-H-5-methyl-7-oxo]1,2,4[triazolo[1,5-a]pyrimidine)₂](Navarro et al., J. Med. Chem. 41(3): 332-338, 1998),[Pt(cis-1,4-DACH)(trans-C[₂)(CBDCA)]. 1/2MeOH cisplatin (Shamsuddin etal., Inorg. Chem. 36(25): 5969-5971, 1997), 4-pyridoxate diamminehydroxy platinum (Tokunaga et al., Pharm. Sci. 3(7): 353-356, 1997),Pt(II) . . . Pt(II) (Pt₂[NHCHN(C(CH₂)(CH₃))]₄) (Navarro et al., Inorg.Chem. 35(26): 7829-7835, 1996), 254-S cisplatin analogue (Koga et al.,Neurol. Res. 18(3): 244-247, 1996), o-phenylenediamine ligand bearingcisplatin analogues (Koeckerbauer & Bednarski, J. Inorg. Biochem. 62(4):281-298, 1996), trans, cis-[Pt(OAc)₂I₂(en)] (Kratochwil et al., J. Med.Chem. 39(13): 2499-2507, 1996), estrogenic 1,2-diarylethylenediamineligand (with sulfur-containing amino acids and glutathione) bearingcisplatin analogues (Bednarski, J. Inorg. Biochem. 62(1): 75, 1996),cis-1,4-diaminocyclohexane cisplatin analogues (Shamsuddin et al., J.Inorg. Biochem. 61(4): 291-301, 1996), 5′ orientational isomer ofcis-[Pt(NH₃)(4-aminoTEMP-O){d(GpG)}] (Dunham & Lippard, J. Am. Chem.Soc. 117(43): 10702-12, 1995), chelating diamine-bearing cisplatinanalogues (Koeckerbauer & Bednarski, J. Pharm. Sci. 84(7): 819-23,1995), 1,2-diarylethyleneamine ligand-bearing cisplatin analogues (Ottoet al., J. Cancer Res. Clin. Oncol. 121(1): 31-8, 1995),(ethylenediamine)platinum(II) complexes (Pasini et al., J. Chem. Soc.,Dalton Trans. 4: 579-85, 1995), C₁₋₉₇₃ cisplatin analogue (Yang et al.,Int. J. Oncol. 5(3): 597-602, 1994), cis-diaminedichloroplatinum(II) andits analoguescis-1,1-cyclobutanedicarbosylato(2R)-2-methyl-1,4-butanediamineplatinum(II)and cis-diammine(glycolato)platinum (Claycamp & Zimbrick, J. Inorg.Biochem. 26(4): 257-67, 1986; Fan et al., Cancer Res. 48(11): 3135-9,1988; Heiger-Bernays et al., Biochemistry 29(36): 8461-6, 1990; Kikkawaet al., J. Exp. Clin. Cancer Res. 12(4): 233-40, 1993; Murray et al.,Biochemistry 31(47): 11812-17, 1992; Takahashi et al., Cancer Chemother.Pharmacol. 33(1): 31-5, 1993),cis-amine-cyclohexylamine-dichloroplatinum(II) (Yoshida et al., Biochem.Pharmacol. 48(4): 793-9, 1994), gem-diphosphonate cisplatin analogues(FR 2683529),(meso-1,2-bis(2,6-dichloro-4-hydroxyplenyl)ethylenediamine)dichloroplatinum(II) (Bednarski et al., J. Med. Chem. 35(23): 4479-85,1992), cisplatin analogues containing a tethered dansyl group (Hartwiget al., J. Am. Chem. Soc. 114(21): 8292-3, 1992), platinum(II)polyamines (Siegmann et al., Inorg. Met.-Containing Polym. Mater.,(Proc. Am. Chem. Soc. Int. Symp.), 335-61, 1990),cis-(3H)dichloro(ethylenediamine)platinum(II) (Eastman, Anal. Biochem.197(2): 311-15, 1991), trans-diamminedichloroplatinum(II) andcis-(Pt(NH₃)₂(N₃-cytosine)Cl) (Bellon & Lippard, Biophys. Chem. 35(2-3):179-88, 1990), 3H-cis-1,2-diaminocyclohexanedichloroplatinum(II) and3H-cis-1,2-diaminocyclohexane-malonatoplatinum (II) (Oswald et al., Res.Commun. Chem. Pathol. Pharmacol. 64(1): 41-58, 1989),diaminocarboxylatoplatinum (EPA 296321),trans-(D,1)-1,2-diaminocyclohexane carrier ligand-bearing platinumanalogues (Wyrick & Chaney, J. Labelled Compd. Radiopharm. 25(4):349-57, 1988), aminoalkylaminoanthraquinone-derived cisplatin analogues(Kitov et al., Eur. J. Med. Chem. 23(4): 381-3, 1988), spiroplatin,carboplatin, iproplatin and JM40 platinum analogues (Schroyen et al.,Eur. J. Cancer Clin. Oncol. 24(8): 1309-12, 1988), bidentate tertiarydiamine-containing cisplatinum derivatives (Orbell et al., Inorg. Chim.Acta 152(2): 125-34, 1988), platinum(II), platinum(IV) (Liu & Wang,Shandong Yike Daxue Xuebao 24(1): 35-41, 1986),cis-diammine(1,1-cyclobutanedicarboxylato-)platinum(II) (carboplatin,JM8) and ethylenediammine-malonatoplatinum(II) (JM40) (Begg et al.,Radiother. Oncol. 9(2): 157-65, 1987), JM8 and JM9 cisplatin analogues(Harstrick et al., Int J. Androl. 10(1); 139-45, 1987),(NPr4)₂((PtCL4).cis-(PtCl2—(NH2Me)₂)) (Brammer et al., J. Chem. Soc.,Chem. Commun. 6: 443-5, 1987), aliphatic tricarboxylic acid platinumcomplexes (EPA 185225), and cis-dichloro(aminoacid)(tert-butylamine)platinum(II) complexes (Pasini & Bersanetti,Inorg. Chim. Acta 107(4): 259-67, 1985). These compounds are thought tofunction by binding to DNA, i.e., acting as alkylating agents of DNA.

As medical implants are made in a variety of configurations and sizes,the exact dose administered will vary with device size, surface area,design and portions of the implant coated. However, certain principlescan be applied in the application of this art. Drug dose can becalculated as a function of dose per unit area (of the portion of thedevice being coated), total drug dose administered can be measured andappropriate surface concentrations of active drug can be determined.Regardless of the method of application of the drug to the medicalimplant, the preferred anticancer/anti-infective agents, used alone orin combination, should be administered under the following dosingguidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the implant components, or applied without acarrier polymer, the total dose of doxorubicin applied to the implantshould not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularlypreferred embodiment, the total amount of drug applied should be in therange of 1 μg to 5 mg. The dose per unit area (i.e., the amount of drugas a function of the surface area of the portion of the implant to whichdrug is applied and/or incorporated) should fall within the range of0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, doxorubicin should be applied to the implant surface at adose of 0.1 μg/mm²-10 μg/mm². As different polymer and non-polymercoatings will release doxorubicin at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the implant surface such that a minimum concentration of10⁻⁷-10⁻⁴ M of doxorubicin is maintained on the surface. It is necessaryto insure that surface drug concentrations exceed concentrations ofdoxorubicin known to be lethal to multiple species of bacteria and fungi(i.e., are in excess of 10⁻⁴ M; although for some embodiments lowerconcentrations are sufficient). In a preferred embodiment, doxorubicinis released from the surface of the implant such that anti-infectiveactivity is maintained for a period ranging from several hours toseveral months. In a particularly preferred embodiment the drug isreleased in effective concentrations for a period ranging from 1 week-6months. It should be readily evident based upon the discussions providedherein that analogues and derivatives of doxorubicin (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asdoxorubicin is administered at half the above parameters, a compoundhalf as potent as doxorubicin is administered at twice the aboveparameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the implant, or applied without a carrier polymer, the total dose ofmitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg).In a particularly preferred embodiment, the total amount of drug appliedshould be in the range of 0.1 μg to 1 mg. The dose per unit area (i.e.,the amount of drug as a function of the surface area of the portion ofthe implant to which drug is applied and/or incorporated) should fallwithin the range of 0.01 μg-20 μg per mm² of surface area. In aparticularly preferred embodiment, mitoxantrone should be applied to theimplant surface at a dose of 0.05 μg/mm²-3 μg/mm². As different polymerand non-polymer coatings will release mitoxantrone at differing rates,the above dosing parameters should be utilized in combination with therelease rate of the drug from the implant surface such that a minimumconcentration of 10⁻⁵-10⁻⁶ M of mitoxantrone is maintained. It isnecessary to insure that drug concentrations on the implant surfaceexceed concentrations of mitoxantrone known to be lethal to multiplespecies of bacteria and fungi (i.e., are in excess of 10⁻⁵ M; althoughfor some embodiments lower drug levels will be sufficient). In apreferred embodiment, mitoxantrone is released from the surface of theimplant such that anti-infective activity is maintained for a periodranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 week-6 months. It should be readily evidentbased upon the discussions provided herein that analogues andderivatives of mitoxantrone (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as mitoxantrone is administered athalf the above parameters, a compound half as potent as mitoxantrone isadministered at twice the above parameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the implant, or applied without a carrierpolymer, the total dose of 5-fluorouracil applied should not exceed 250mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment,the total amount of drug applied should be in the range of 10 μg to 25mg. The dose per unit area (i.e., the amount of drug as a function ofthe surface area of the portion of the implant to which drug is appliedand/or incorporated) should fall within the range of 0.1 μg-1 mg per mm²of surface area. In a particularly preferred embodiment, 5-fluorouracilshould be applied to the implant surface at a dose of 1.0 μg/mm²-50μg/mm². As different polymer and non-polymer coatings will release5-fluorouracil at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from theimplant surface such that a minimum concentration of 10⁻⁴-10⁻⁷ M of5-fluorouracil is maintained. It is necessary to insure that surfacedrug concentrations exceed concentrations of 5-fluorouracil known to belethal to numerous species of bacteria and fungi (i.e., are in excess of10⁻⁴ M; although for some embodiments lower drug levels will besufficient). In a preferred embodiment, 5-fluorouracil is released fromthe implant surface such that anti-infective activity is maintained fora period ranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 week-6 months. It should be readily evidentbased upon the discussions provided herein that analogues andderivatives of 5-fluorouracil (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as 5-fluorouracil is administered athalf the above parameters, a compound half as potent as 5-fluorouracilis administered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the cardiac implant, or applied without a carrierpolymer, the total dose of etoposide applied should not exceed 25 mg(range of 0.1 μg to 25 mg). In a particularly preferred embodiment, thetotal amount of drug applied should be in the range of 1 μg to 5 mg. Thedose per unit area (i.e., the amount of drug as a function of thesurface area of the portion of the implant to which drug is appliedand/or incorporated) should fall within the range of 0.01 μg-100 μg permm² of surface area. In a particularly preferred embodiment, etoposideshould be applied to the implant surface at a dose of 0.1 μg/mm²-10μg/mm². As different polymer and non-polymer coatings will releaseetoposide at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from theimplant surface such that a concentration of 10⁻⁵-10⁻⁶ M of etoposide ismaintained. It is necessary to insure that surface drug concentrationsexceed concentrations of etoposide known to be lethal to a variety ofbacteria and fungi (i.e., are in excess of 10⁻⁵ M; although for someembodiments lower drug levels will be sufficient). In a preferredembodiment, etoposide is released from the surface of the implant suchthat anti-infective activity is maintained for a period ranging fromseveral hours to several months. In a particularly preferred embodimentthe drug is released in effective concentrations for a period rangingfrom 1 week-6 months. It should be readily evident based upon thediscussions provided herein that analogues and derivatives of etoposide(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as etoposide is administered at half the above parameters, acompound half as potent as etoposide is administered at twice the aboveparameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate and/or podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of theimplant coating. Similarly anthracyclines (e.g., doxorubicin ormitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acidantagonists (e.g., methotrexate and/or podophylotoxins (e.g., etoposide)can be combined with traditional antibiotic and/or antifungal agents toenhance efficacy. The anti-infective agent may be further combined withantithrombotic and/or antiplatelet agents (for example, heparin, dextransulphate, danaparoid, lepirudin, hirudin, AMP, adenosine,2-chloroadenosine, aspirin, phenylbutazone, indomethacin, meclofenamate,hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel,abcixamab, eptifibatide, tirofiban, streptokinase, and/or tissueplasminogen activator) to enhance efficacy.

C. Methods for Generating Medical Devices which Contain or Release aFibrosis-Inducing Agent

In the practice of this invention, drug-coated, drug-impregnated, ordrug containing implants and medical devices are provided which induceadhesion or fibrosis in the surrounding tissue, or facilitate“anchoring” of the device/implant in situ, thus enhancing the efficacy.Within various embodiments, fibrosis is induced by local or systemicrelease of specific pharmacological agents that become localized to thetissue adjacent to the device or implant. There are numerous methodsavailable for optimizing delivery of the fibrosis-inducing agent to thesite of the intervention and several of these are described below.

1) Devices and Implants that Contain or Release Fibrosis-Inducing Agents

Medical devices or implants of the present invention contain and/or areadapted to release an agent which induces fibrosis or adhesion to thesurrounding tissue. Medical devices or implants may be adapted to haveincorporated into their structure a fibrosis-inducing agent, adapted tohave a surface coating of a fibrosis-inducing agent and/or adapted torelease a fibrosis-inducing agent by (a) directly affixing to theimplant or device a desired fibrosis-inducing agent or compositioncontaining the fibrosis-inducing agent (e.g., by either spraying themedical implant with a drug and/or carrier (polymeric ornon-polymeric)-drug composition to create a film or coating on all, orparts of the internal or external surface of the device; by dipping theimplant or device into a drug and/or carrier (polymeric ornon-polymeric)-drug solution to coat all or parts of the device orimplant; or by other covalent or non-covalent (e.g., mechanicallyattached via knotting or the use of an adhesive or thermal treatment,electrostatic, ionic, hydrogen bonded or hydrophobic interactions)attachment of the therapeutic agent to the device or implant surface);(b) by coating the medical device or implant with a substance such as ahydrogel which can in turn absorb the desired fibrosis-inducing agent orcomposition; (c) by interweaving a “thread” composed of, or coated with,the fibrosis-inducing agent into the medical implant or device (e.g., apolymeric strand composed of materials that induce fibrosis (e.g., silk,collagen, EVA, PLA, polyurethanes, polymerized drug compositions) orpolymers which comprise and/or release a fibrosis-inducing agent fromthe thread); (d) by covering all, or portions of the device or implantwith a sleeve, cover or mesh containing a fibrosis-inducing agent (i.e.,a covering comprised of a fibrosis-inducing agent—polymers such as silk,collagen, EVA, PLA, polyurethanes or polymerized compositions containingfibrosis-inducing agents); (e) constructing all, or parts of the deviceor implant itself with the desired agent or composition (e.g.,constructing the device from polymers such as silk, collagen, EVA, PLA,polyurethanes or polymerized compositions of fibrosis-inducing agents);(f) otherwise impregnating the device or implant with the desiredfibrosis-inducing agent or composition; (g) scoring (i.e., creatingridges or indentations) on all, or parts, of the device or implantsurface to produce irritation of the tissue and ultimately fibrosis; (h)composing all, or parts, of the device or implant from metal alloys thatinduce fibrosis (e.g., copper); (i) constructing all, or parts of thedevice or implant itself from a degradable or non-degradable polymerthat releases one or more fibrosis-inducing agents; (j) utilizingspecialized multi-drug releasing medical device systems (described,e.g., in U.S. Pat. No. 6,562,065; U.S. Patent Application PublicationNos. 2003/0199970 and 2003/0167085; and in PCT Publication Nos. WO03/015664 and WO 02/32347) to deliver fibrosis-inducing agents alone orin combination.

In one aspect, a medical device may be modified by attaching fibers(threads) to the surface of the device. The fibers may be polymericand/or may be formed of or coated with a fibrosing material, such assilk. For example, the threads may be formed from a silk suturematerial. The presence of the threads can result in an enhanced cellularand/or extracellular matrix response to the exterior of the device. Thethreads can be attached to the device by using any one or a combinationof the following methods, including use of an adhesive, thermal welding,stitching, wrapping, weaving, knotting, and the like. The threads can becoated with a material that delays the time it takes for the threadmaterial to come into contact with the surrounding tissue and blood,thus allowing placement of the device without concern of thromboticevents due to the presence of the polymeric threads. Examples ofmaterials that can be used to prepare coatings capable of degrading ordissolving upon implantation include gelatin, polyesters (e.g., PLGA,PLA, MePEG-PLGA, PLGA-PEG-PLGA, and blends thereof), lipids, fattyacids, sugar esters, nucleic acid esters, polyanhydrides,polyorthoesters, and PVA. The coating may further contain a fibrosingagent and/or a biologically active agent that may, for example, reducethe probability of an immediate thrombotic event (e.g., heparin,hydrophobic quaternary amine heparin complexes, and the like). Inaddition to the polymeric threads, all or a portion of the device may becoated with a polymeric carrier that contains a fibrosis-inducing agent.

The fibers (threads) may further comprise a coating or composition thatis affected by an applied magnetic field. For example, a device such asa stent graft may be coated with polymeric threads that are coated,contain, or are formed from a fibrosing agent (e.g., silk suture). Amagnetic field can be applied to the coated device to orient and alignthe polymeric fibers relative to each other and the surface of thedevice to increase the surface area of the fibers exposed to biologicalmediators which would stimulate a fibrotic reaction. The magneticallyactive component can be associated with the polymeric fiber using avariety of methods. The magnetically active component may beincorporated during manufacture of the fiber, for example, byincorporating a magnetically active material such as magnetite into apolymer feed prior to extrusion of the polymeric fiber. The magneticallyactive component can be coated onto the entire fiber or a portion of thefiber using, for example, an adhesive or a polymeric coating. Thepolymeric fiber (or a portion thereof) can be heated or plasticized witha solvent and then rolled in the magnetically active component, suchthat the magnetic material protrudes above the surface of the fiber oris embedded into the surface of the fiber.

The threads (either with or without a magnetic component) may beattached to the device in various configurations that can result ineither partial or complete coverage of the exterior of the device. Thepolymeric threads may be affixed to the ends of a device or to thecentral portion of a device, and the attachment may be in a vertical,horizontal, or diagonal manner.

2) Systemic, Regional and Local Delivery of Fibrosis-inducing Agents

A variety of drug-delivery technologies are available for systemic,regional and local delivery of therapeutic agents. Several of thesetechniques may be suitable to achieve preferentially elevated levels offibrosis-inducing agents in the vicinity of the medical device orimplant, including: (a) using drug-delivery catheters for local,regional or systemic delivery of fibrosing agents to the tissuesurrounding the device or implant (typically, drug delivery cathetersare advanced through the circulation or inserted directly into tissuesunder radiological guidance until they reach the desired anatomicallocation; the fibrosing agent can then be released from the catheterlumen in high local concentrations in order to deliver therapeutic dosesof the drug to the tissue surrounding the device or implant); (b) druglocalization techniques such as magnetic, ultrasonic or MRI-guided drugdelivery; (c) chemical modification of the fibrosis-inducing drug orformulation designed to increase uptake of the agent into damagedtissues (e.g., modification of the drug or formulation to includeantibodies directed against damaged or healing tissue components such asmacrophages, neutrophils, smooth muscle cells, fibroblasts,extracellular matrix components, neovascular tissue); (d) chemicalmodification of the fibrosis-inducing drug or formulation designed tolocalize the drug to areas of bleeding or disrupted vasculature such asencapsulation of the drug into site directed liposomes; and/or (e)direct injection of the fibrosis-inducing agent, for example underendoscopic vision.

3) Infiltration of Fibrosis-Inducing Agents into the Tissue Surroundinga Device or Implant

Alternatively, the tissue cavity into which the device or implant isplaced can be treated with a fibrosis-inducing agent prior to, during,or after the implantation procedure. This can be accomplished in severalways including: (a) topical application of the fibrosing agent into theanatomical space where the device can be placed (particularly useful forthis embodiment is the use of polymeric carriers which release thefibrosing agent over a period ranging from several hours to severalweeks—fluids, suspensions, emulsions, microemulsions, microspheres,pastes, gels, microparticulates, sprays, aerosols, solid implants andother formulations which release a fibrosing agent can be delivered intothe region where the device or implant can be inserted via specializeddelivery catheters or other applicators); (b) microparticulate silkand/or silk strands (e.g., linear, branched, and/or coiled) are alsouseful for directed delivery into the implantation site; (c) sprayablecollagen-containing formulations such as COSTASIS (AngiotechPharmaceuticals, Inc., Vancouver, BC) or materials made from 4-armedthiol PEG (10K), a 4-armed NHS PEG(10K) and methylated collagen(described below), or materials made from 4-armed thiol PEG (10K), a4-armed NHS PEG(10K) and collagen or gelatin, either alone, or loadedwith a fibrosis-inducing agent, applied to the implantation site (or theimplant/device surface); (d) sprayable in situ forming PEG-containingformulations such as COSEAL (Angiotech Pharmaceuticals, Inc., Canada),FOCALSEAL (Genzyme Corporation, Cambridge, Mass.), SPRAYGEL or DURASEAL(both from Confluent Surgical, Inc., Waltham, Mass.), either alone, orloaded with a fibrosis-inducing agent, applied to the implantation site(or the implant/device surface);

-   -   (e) fibrinogen-containing formulations such as FLOSEAL or        TISSEAL (both from Baxter Healthcare Corporation; Fremont,        Calif.), either alone, or loaded with a fibrosis-inducing agent,        applied to the implantation site (or the implant/device        surface); (f) hyaluronic acid-containing formulations (either        non-crosslinked, crosslinked or chemically modified) such as        PERLANE or RESTYLANE (both from Q-Med AB, Sweden), HYLAFORM        (Inamed Corporation; Santa Barbara, Calif.), SYNVISC (Biomatrix,        Inc.; Ridgefied, N.J.), SEPRAFILM or SEPRACOAT (both from        Genzyme Corporation; Cambridge, Mass.) loaded with a fibrosis        with a fibrosis-inducing agent applied to the implantation site        (or the implant/device surface); (g) polymeric gels for surgical        implantation such as REPEL (Life Medical Sciences, Inc.;        Princeton, N.J.) or FLOWGEL (Baxter Healthcare Corporation,        Deerfield, Ill.) loaded with a fibrosis-inducing agent applied        to the implantation site (or the implant/device surface); (h)        orthopedic “cements” used to hold prostheses and tissues in        place loaded with a fibrosis-inducing agent applied to the        implantation site (or the implant/device surface), such as        OSTEOBOND (Zimmer, Inc., Warsaw, Ind.), LVC (Wright Medical        Technology, Inc., Arlington, Tenn.), SIMPLEX P (Stryker        Corporation, Kalamazoo, Mich.), PALACOS (Smith & Nephew PLC        Corporation, United Kingdom), and ENDURANCE (Johnson & Johnson,        Inc., New Brunswick, N.J.); (i) surgical adhesives containing        one or more cyanoacrylate monomers (e.g., methyl cyanoacrylate,        ethyl cyanoacrylate, butyl cyanoacrylate, octyl cyanoacrylate,        methoxypropyl cyanoacrylate) such as DERMABOND (Johnson &        Johnson, Inc.), INDERMIL (United States Surgical; Norwalk,        Conn.), GLUSTITCH (Blacklock Medical Products, Inc., Canada) or        TISSUMEND II (Veterinary Products Laboratories; Phoenix, Ariz.),        VETBOND (3M Company; St. Paul, Minn.), TISSUEMEND (TEI        Biosciences, Inc.; Boston, Mass.), HISTOACRYL or HISTOACRYL BLUE        (Davis & Geck; St. Louis, Mo.) and ORABASE SOOTHE-N-SEAL LIQUID        PROTECTANT (Colgate-Palmolive Company; New York; N.Y.), either        alone, or loaded with a fibrosis-inducing agent, applied to the        implantation site (or the implant/device surface); (j) implants        containing hydroxyapatite (or synthetic bone material such as        calcium sulfate, VITOSS and CORTOSS (both from Orthovita, Inc.,        Malvern, Pa.)) loaded with a fibrosis-inducing agent applied to        the implantation site (or the implant/device surface); (k) other        biocompatible tissue fillers loaded with a fibrosis-inducing        agent, such as those made by BioCure, Inc. (Norcross, Ga.), 3M        Company and Neomend, Inc. (Sunnyvale, Calif.), loaded with a        fibrosis-inducing agent applied to the implantation site (or the        implant/device surface); (l) polysaccharide gels such as the        ADCON series of gels (Gliatech, Inc.; Cleveland, Ohio); (m)        films, sponges or meshes such as INTERCEED or VICRYL mesh        (Ethicon, Inc., a Johnson & Johnson Company, Somerville, N.J.),        and GELFOAM (Pharmacia & Upjohn Company; Kalamazoo, Mich.)        loaded with a fibrosis-inducing agent applied to the        implantation site (or the implant/device surface); (n) a        hydrogel that is formed from an amino-functionalized        polyethylene glycol (e.g., 4-armed tetra-amino PEG [10k]) and a        4-armed NHS functionalized PEG (e.g., pentaerythritol        poly(ethylene glycol)ether tetra-succinimidyl glutarate [10K]).        This hydrogel may further contain collagen, methylated collagen        and/or gelatin. This hydrogel can further comprise the        fibrosis-inducing agents described above (e.g., silk powder or        silk threads), and (O) compositions that enhance        osteointegration and/or osteogenesis, including materials        composed of beta-tricalcium phosphate (e.g., VITOSS, PROOSTEON        500R made by E-Interpore-Cross International), hydroxyapatite or        Ca₁₀(PO₄)₆OH (e.g., OSTEOGRAF made by Ceramed Denta, Inc.,        Lakewood, Colo.), calcium carbonate or CaCO₃, calcium sulfate        (e.g., OSTEOSET and ALLOMATRIX made by Wright Medical        Technology, Inc.), calcium phosphate (e.g., CALCIBON made by        Merck & Co., Inc., Whitehouse Station, N.J., NORIAN SRS made by        Synthes-Strates, Switzerland), as well as synthetic bone fillers        (e.g., CORTOSS and processed bone fillers, e.g., BIOOSS made by        Geistlich Biomaterials, Inc., Switzerland). Representative        examples of these materials are described in U.S. Pat. Nos.        3,929,971, 4,861,733; 6,527,810; 4,772,468; 4,882,149;        5,167,961; 6,576,015; 4,839,215; 5,614,206; 5,807,567;        6,030,636; 6,652,887; 6,206,957; 6,485,754; 4,347,234;        4,291,013; 5,129,905; 5,336,264; 5,569,442; 5,571,493;        5,683,667; 5,709,742; 5,820,632; 5,658,332; 5,681,872;        5,914,356; 5,939,039; 6,325,987; 6,383,519; 6,458,162;        6,736,799; 6,521,246; and 6,709,744.

In one aspect, the fibrosis-inducing agent may be delivered as asolution. The fibrosis-inducing agent can be incorporated directly intothe solution to provide a homogeneous solution or dispersion. In certainembodiments, the solution is an aqueous solution. The aqueous solutionmay further include buffer salts, as well as viscosity modifying agents(e.g., hyaluronic acid, alginates, CMC, and the like). In another aspectof the invention, the solution can include a biocompatible solvent, suchas ethanol, DMSO, glycerol, PEG-200, PEG-300 or NMP.

4) Coating and Sustained-Release Preparations of Fibrosis-InducingAgents

For many of the aforementioned embodiments, the fibrosis-inducing agentcan be incorporated or coated onto the device. For example, a desiredfibrosis-inducing agent may be admixed with, blended with, conjugatedto, or, otherwise modified to contain a polymeric composition (which maybe either biodegradable or non-biodegradable) or non-polymericcomposition. The polymeric or non-polymeric composition (i.e., carrier)can be used to coat the device or as a component of the materials usedto manufacture the device. In other embodiments, the localized sustaineddelivery of the fibrosis inhibiting agent may be required. For example,a desired fibrosis-inducing agent may be admixed with, blended with,conjugated to, or, otherwise modified to contain a polymeric composition(which may be either biodegradable or non-biodegradable) ornon-polymeric composition in order to release the fibrosis-inducingagent over a period of time. For the above embodiments, biodegradableand non-biodegradable polymers, polymer conjugates as well asnon-polymeric materials can be used to accomplish the incorporation ofthe fibrosis-inducing agent onto or into the device.

Representative examples of biodegradable polymers suitable for thedelivery of fibrosis-inducing agents include albumin, collagen, gelatin,hyaluronic acid, starch, cellulose and cellulose derivatives (e.g.,methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, cellulose acetate phthalate, cellulose acetatesuccinate, hydroxypropylmethylcellulose phthalate), casein, dextrans,polysaccharides, fibrinogen, poly(ether ester) multiblock copolymers,based on poly(ethylene glycol) and poly(butylene terephthalate),tyrosine-derived polycarbonates (e.g., U.S. Pat. No. 6,120,491),poly(hydroxyl acids), poly(D,L-lactide), poly(D,L-lactide-co-glycolide),poly(glycolide), poly(hydroxybutyrate), polydioxanone,poly(alkylcarbonate) and poly(orthoesters), polyesters,poly(hydroxyvaleric acid), polydioxanone, poly(ethylene terephthalate),poly(malic acid), poly(tartronic acid), poly(acrylamides),polyanhydrides, poly(ester-amides), poly(ester-imides),poly(ester-ureas), poly(ester-urethane-ureas), poly(anhydride-esters),poly(anhydride-imides), polyphosphazenes, poly(amino acids),poly(alkylene oxide)-poly(ester) block copolymers (e.g., X—Y, X—Y—X orY—X—Y, where X is a polyalkylene oxide and Y is a polyester (e.g., PLGA,PLA, PCL, polydioxanone and copolymers thereof), and copolymers as wellas blends thereof. (see generally, Ilium, L., Davids, S. S. (eds.)“Polymers in Controlled Drug Delivery” Wright, Bristol, 1987; Arshady,J. Controlled Release 17: 1-22, 1991; Pitt, Int. J. Phar. 59: 173-196,1990; Holland et al., J. Controlled Release 4: 155-0180, 1986).

Representative examples of non-degradable polymers suitable for thedelivery of fibrosis-inducing agents include poly(ethylene-co-vinylacetate) (“EVA”) copolymers, silicone rubber, acrylic polymers (e.g.,polyacrylic acid, polymethylacrylic acid, polymethylmethacrylate,poly(butyl methacrylate)), poly(alkylcyanoacrylate) (e.g.,poly(ethylcyanoacrylate), poly(butylcyanoacrylate),poly(hexylcyanoacrylate), and poly(octylcyanoacrylate)), polyethylene,polypropylene, polyamides (nylon 6,6), polyurethanes (includinghydrophilic polyurethanes), poly(ester-urethanes),poly(ether-urethanes), poly(ester-urea), poly(carbonate urethane)s,polyethers (poly(ethylene oxide), poly(propylene oxide), polyoxyalkyleneether block copolymers based on ethylene oxide and propylene oxide suchas PLURONICs and PLURONICs R and poly(tetramethylene glycol)),styrene-based polymers (polystyrene, poly(styrene sulfonic acid),poly(styrene)-block-poly(isobutylene)-block-poly(styrene),poly(styrene)-poly(isoprene) block copolymers], and vinyl polymers(polyvinylpyrrolidone, poly(vinyl alcohol), poly(vinyl acetatephthalate) as well as copolymers and blends thereof. Polymers may alsobe developed which are either anionic (e.g., alginate, carrageenan,carboxymethyl cellulose, poly(acrylamido-2-methyl propane sulfonic acid)and copolymers thereof, poly(methacrylic acid) and copolymers thereof,and poly(acrylic acid) and copolymers thereof, as well as blendsthereof) or cationic (e.g., chitosan, poly-L-lysine, polyethylenimine,and poly(allyl amine) and blends thereof (see generally, Dunn et al., J.Applied Polymer Sci. 50: 353-365, 1993; Cascone et al., J. MaterialsSci.: Materials in Medicine 5: 770-774, 1994; Shiraishi et al., Biol.Pharm. Bull. 16(11): 1164-1168, 1993; Thacharodi and Rao, Int'l J.Pharm. 120: 115-118, 1995; Miyazaki et al., Intl J. Pharm. 118: 257-263,1995).

Particularly preferred polymeric carriers include poly(ethylene-co-vinylacetate), cellulose esters (nitrocellulose), poly(hydroxymethacrylate),poly(methylmethacrylate), poly(ethylene-co-acrylic acid),poly(vinylpyrrolidone) polyurethanes (e.g., CHRONOFLEX AL and CHRONOFLEXAR (both from CardioTech International, Inc., Woburn, Mass.) and BIONATE(Polymer Technology Group, Inc., Emeryville, Calif.), poly(D,L-lacticacid) oligomers and polymers, poly(L-lactic acid) oligomers andpolymers, poly(glycolic acid), copolymers of lactic acid and glycolicacid, poly(caprolactone), poly(valerolactone), polyanhydrides,poly(anhydride esters), poly(ester-amides), poly(ester-ureas),copolymers of poly(caprolactone) or poly(lactic acid) with apolyethylene glycol (e.g., MePEG), silicone rubbers,poly(styrene)block-poly(isobutylene)-block-poly(styrene), poly(acrylate)polymers, and blends, admixtures, or co-polymers of any of the above.Other preferred polymers include collagen, poly(alkylene oxide)-basedpolymers, polysaccharides such as hyaluronic acid, chitosan and fucans,and copolymers of polysaccharides with degradable polymers, as well ascrosslinked compositions of the above.

Other representative polymers capable of sustained localized delivery offibrosis-inducing agents include carboxylic polymers, polyacetates,polyacrylamides, polycarbonates, polyethers, substituted polyethylenes,polyvinylbutyrals, polysilanes, polyureas, polyoxides, polystyrenes,polysulfides, polysulfones, polysulfonides, polyvinylhalides,pyrrolidones, isoprene rubbers, thermal-setting polymers, cross-linkableacrylic and methacrylic polymers, ethylene acrylic acid copolymers,styrene acrylic copolymers, vinyl acetate polymers and copolymers, vinylacetal polymers and copolymers, epoxies, melamines, other amino resins,phenolic polymers, and copolymers thereof, water-insoluble celluloseester polymers (including cellulose acetate propionate, celluloseacetate, nitrocellulose, cellulose acetate butyrate, cellulose nitrate,cellulose acetate phthalate, and mixtures thereof), polyvinylpyrrolidone(pvp), polyethylene glycols, polyethylene oxides, polyvinyl alcohol,polyethers, polyhydroxyacrylate, dextran, xanthan, hydroxypropylcellulose, methyl cellulose, and homopolymers and copolymers ofN-vinylpyrrolidone, N-vinyllactam, N-vinyl butyrolactam, N-vinylcaprolactam, other vinyl compounds having polar pendant groups, acrylateand methacrylate having hydrophilic esterifying groups, hydroxyacrylate,and acrylic acid, and combinations thereof; cellulose esters and ethers,ethyl cellulose, nitro-cellulose, hydroxyethyl cellulose, cellulosenitrate, cellulose acetate, cellulose acetate butyrate, celluloseacetate propionate, polyacrylate, natural and synthetic elastomers,acetal, styrene polybutadiene, acrylic resin, polyvinylidene chloride,polycarbonate, homopolymers and copolymers of vinyl compounds,polyvinylchloride, and polyvinylchloride acetate.

Representative examples of patents relating to drug-delivery polymersand their preparation include PCT Publication Nos. WO 98/19713, WO01/17575, WO 01/41821, WO 01/41822, and WO 01/15526 (as well as theircorresponding U.S. applications), and U.S. Pat. Nos. 4,500,676,4,582,865, 4,629,623, 4,636,524, 4,713,448, 4,795,741, 4,913,743,5,069,899, 5,099,013, 5,128,326, 5,143,724, 5,153,174, 5,246,698,5,266,563, 5,399,351, 5,525,348, 5,800,412, 5,837,226, 5,942,555,5,997,517, 6,007,833, 6,071,447, 6,090,995, 6,106,473, 6,110,483,6,121,027, 6,156,345, 6,214,901, 6,368,611 6,630,155, 6,528,080,RE37,950, 6,46,1631, 6,143,314, 5,990,194, 5,792,469, 5,780,044,5,759,563, 5,744,153, 5,739,176, 5,733,950, 5,681,873, 5,599,552,5,340,849, 5,278,202, 5,278,201, 6,589,549, 6,287,588, 6,201,072,6,117,949, 6,004,573, 5,702,717, 6,413,539, and 5,714,159, 5,612,052 andU.S. Patent Application Publication Nos. 2003/0068377, 2002/0192286,2002/0076441, and 2002/0090398.

It should be obvious to one of skill in the art that the polymers asdescribed herein can also be blended or copolymerized in variouscompositions as required to deliver therapeutic doses offibrosis-inducing agents to blood vessels in the treatment site.

Polymeric carriers for fibrosis-inducing agents can be fashioned in avariety of forms, with desired release characteristics and/or withspecific properties depending upon the device, composition or implantbeing utilized. For example, polymeric carriers may be fashioned torelease a fibrosis-inducing agent upon exposure to a specific triggeringevent such as pH (see, e.g., Heller et al., “Chemically Self-RegulatedDrug Delivery Systems,” in Polymers in Medicine III, Elsevier SciencePublishers B.V., Amsterdam, 1988, pp. 175-188; Kang et al., J. AppliedPolymer Sci. 48: 343-354, 1993; Dong et al., J. Controlled Release 19:171-178, 1992; Dong and Hoffman, J. Controlled Release 15: 141-152,1991; Kim et al., J. Controlled Release 28: 143-152, 1994; Cornejo-Bravoet al., J. Controlled Release 33: 223-229, 1995; Wu and Lee, Pharm. Res.10(10): 1544-1547, 1993; Serres et al., Pharm. Res. 13(2): 196-201,1996; Peppas, “Fundamentals of pH- and Temperature-Sensitive DeliverySystems,” in Gurny et al. (eds.), Pulsatile Drug Delivery,Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1993, pp. 41-55;Doelker, “Cellulose Derivatives,” 1993, in Peppas and Langer (eds.),Biopolymers I, Springer-Verlag, Berlin). Representative examples ofpH-sensitive polymers include poly(acrylic acid) and its derivatives(including for example, homopolymers such as poly(aminocarboxylic acid);poly(acrylic acid); poly(methyl acrylic acid), copolymers of suchhomopolymers, and copolymers of poly(acrylic acid) and acrylmonomerssuch as those discussed above. Other pH sensitive polymers includepolysaccharides such as cellulose acetate phthalate;hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcelluloseacetate succinate; cellulose acetate trimellilate; and chitosan. Yetother pH sensitive polymers include any mixture of a pH sensitivepolymer and a water-soluble polymer.

Likewise, fibrosis-inducing agents can be delivered via polymericcarriers which are temperature sensitive (see, e.g., Chen et al., “NovelHydrogels of a Temperature-Sensitive Pluronic Grafted to a BioadhesivePolyacrylic Acid Backbone for Vaginal Drug Delivery,” in Proceed.Intern. Symp. Control. Rel. Bioact Mater. 22: 167-168, ControlledRelease Society, Inc., 1995; Okano, “Molecular Design ofStimuli-Responsive Hydrogels for Temporal Controlled Drug Delivery,” inProceed. Intern. Symp. Control. Rel. Bioact Mater. 22: 111-112,Controlled Release Society, Inc., 1995; Johnston et al., Pharm. Res.9(3): 425-433, 1992; Tung, Int'l J. Pharm. 107: 85-90, 1994; Harsh andGehrke, J. Controlled Release 17: 175-186, 1991; Bae et al., Pharm. Res.8(4): 531-537, 1991; Dinarvand and D'Emanuele, J. Controlled Release 36:221-227, 1995; Yu and Grainger, “Novel Thermo-sensitive AmphiphilicGels: Poly N-isopropylacrylamide-co-sodiumacrylate-co-n-N-alkylacrylamide Network Synthesis and PhysicochemicalCharacterization,” Dept. of Chemical & Biological Sci., Oregon GraduateInstitute of Science & Technology, Beaverton, Oreg., pp. 820-821; Zhouand Smid, “Physical Hydrogels of Associative Star Polymers,” PolymerResearch Institute, Dept. of Chemistry, College of Environmental Scienceand Forestry, State Univ. of New York, Syracuse, N.Y., pp. 822-823;Hoffman et al., “Characterizing Pore Sizes and Water ‘Structure’ inStimuli-Responsive Hydrogels,” Center for Bioengineering, Univ. ofWashington, Seattle, Wash., p. 828; Yu and Grainger, “Thermo-sensitiveSwelling Behavior in Crosslinked N-isopropylacrylamide Networks:Cationic, Anionic and Ampholytic Hydrogels,” Dept. of Chemical &Biological Sci., Oregon Graduate Institute of Science & Technology,Beaverton, Oreg., pp. 829-830; Kim et al., Pharm. Res. 9(3): 283-290,1992; Bae et al., Pharm. Res. 8(5): 624-628, 1991; Kono et al., J.Controlled Release 30: 69-75, 1994; Yoshida et al., J. ControlledRelease 32: 97-102, 1994; Okano et al., J. Controlled Release 36:125-133, 1995; Chun and Kim, J. Controlled Release 38: 39-47, 1996;D'Emanuele and Dinarvand, Int'l J. Pharm. 118: 237-242, 1995; Katono etal., J. Controlled Release 16: 215-228, 1991; Hoffman, “ThermallyReversible Hydrogels Containing Biologically Active Species,” inMigliaresi et al. (eds.), Polymers in Medicine III, Elsevier SciencePublishers B.V., Amsterdam, 1988, pp. 161-167; Hoffman, “Applications ofThermally Reversible Polymers and Hydrogels in Therapeutics andDiagnostics,” in Third International Symposium on Recent Advances inDrug Delivery Systems, Salt Lake City, Utah, Feb. 24-27, 1987, pp.297-305; Gutowska et al., J. Controlled Release 22: 95-104, 1992;Palasis and Gehrke, J. Controlled Release 18: 1-12, 1992; Paavola etal., Pharm. Res. 12(12): 1997-2002, 1995).

Representative examples of thermogelling polymers, and their gelatintemperature [LCST (° C.)] include homopolymers such aspoly(N-methyl-N-n-propylacrylamide), 19.8; poly(N-n-propylacrylamide),21.5; poly(N-methyl-N-isopropylacrylamide), 22.3;poly(N-n-propylmethacrylamide), 28.0; poly(N-isopropylacrylamide), 30.9;poly(N, n-diethylacrylamide), 32.0; poly(N-isopropylmethacrylamide),44.0; poly(N-cyclopropylacrylamide), 45.5; poly(N-ethylmethyacrylamide),50.0; poly(N-methyl-N-ethylacrylamide), 56.0;poly(N-cyclopropylmethacrylamide), 59.0; and poly(N-ethylacrylamide),72.0. Moreover, thermogelling polymers may be made by preparingcopolymers between (among) monomers of the above, or by combining suchhomopolymers with other water-soluble polymers such as acrylmonomers(e.g., acrylic acid and derivatives thereof, such as methylacrylic acid,acrylate and derivatives thereof, such as butyl methacrylate,acrylamide, and N-n-butyl acrylamide).

Other representative examples of thermogelling polymers includecellulose ether derivatives such as hydroxypropyl cellulose, 41° C.;methyl cellulose, 55° C.; hydroxypropylmethyl cellulose, 66° C.; andethylhydroxyethyl cellulose, polyalkylene oxide-polyester blockcopolymers of the structure X—Y, Y—X—Y and X—Y—X where X is apolyalkylene oxide and Y is a biodegradable polyester (e.g.,PLG-PEG-PLG) and PLURONICS such as F-127, 10-15° C.; L-122, 19° C.;L-92, 26° C.; L-81, 20° C.; and L-61, 24° C.

Representative examples of patents relating to thermally gellingpolymers and their preparation include U.S. Pat. Nos. 6,451,346;6,201,072; 6,117,949; 6,004,573; 5,702,717; and 5,484,610 and PCTPublication Nos. WO 99/07343; WO 99/18142; WO 03/17972; WO 01/82970; WO00/18821; WO 97/15287; WO 01/41735; WO 00/00222 and WO 00/38651.

Fibrosis-inducing agents may be linked by occlusion in the matrices ofthe polymer, bound by covalent linkages, or encapsulated inmicrocapsules. Within certain preferred embodiments of the invention,therapeutic compositions are provided in non-capsular formulations suchas microspheres (ranging from nanometers to micrometers in size),pastes, and threads of various size, films and sprays.

Within certain aspects of the present invention, therapeuticcompositions may be fashioned in any size ranging from 50 nm to 500 μm,depending upon the particular use. These compositions can be in the formof microspheres (porous or non-porous), microparticles, and/ornanoparticles. These compositions can be formed, for example, byspray-drying methods, milling methods, coacervation methods, W/O(water-oil) emulsion methods, W/O/W emulsion methods, and solventevaporation methods. In some embodiments, these compositions can includemicroemulsions, emulsions, liposomes and micelles. Alternatively, suchcompositions may also be readily applied as a “spray”, which solidifiesinto a film or coating for use as a device/implant surface coating or toline the tissues of the implantation site. Such sprays may be preparedfrom microspheres of a wide array of sizes, including for example, from0.1 μm to 3 μm, from 10 μm to 30 μm, and from 30 μm to 100 μm.

Therapeutic compositions of the present invention may also be preparedin a variety of paste or gel forms. For example, within one embodimentof the invention, therapeutic compositions are provided which are liquidat one temperature (e.g., temperature greater than 37° C., such as 40°C., 45° C., 50° C., 55° C. or 60° C.), and solid or semi-solid atanother temperature (e.g., ambient body temperature, or any temperaturelower than 37° C.). Such “thermopastes” may be readily made utilizing avariety of techniques (see, e.g., PCT Publication WO 98/24427). Otherpastes may be applied as a liquid, which solidify in vivo due todissolution of a water-soluble component of the paste and precipitationof encapsulated drug into the aqueous body environment. These pastes andgels containing fibrosis-inducing agents are particularly useful forapplication to the surface of tissues which can be in contact with theimplant or device.

In one aspect, the fibrosing agent or a composition comprising thefibrosing agent may be combined with a film or mesh or may be in theform or a film or mesh.

Films or meshes may take a variety of forms including, but not limitedto, surgical meshes, membranes (e.g., barrier membranes), surgicalsheets, surgical patches, surgical wraps, bandages, liquid bandages,surgical dressings, gauze, fabrics, tapes, surgical membranes, polymermatrices, shells, envelopes, tissue coverings, and other types ofsurgical matrices, and scaffolds.

In one aspect, the device comprises or may be in the form of a film. Thefilm may be formed into one of many geometric shapes. Depending on theapplication, the film may be formed into the shape of a tube or may be athin, elastic sheet of polymer. Generally, films are less than 5, 4, 3,2, or 1 mm thick, more preferably less than 0.75 mm, 0.5 mm, 0.25 mm,or, 0.10 mm thick. Films can also be generated of thicknesses less than50 μm, 25 μm or 10 μm. Films generally are flexible with a good tensilestrength (e.g., greater than 50, preferably greater than 100, and morepreferably greater than 150 or 200 N/cm²), good adhesive properties(i.e., adheres to moist or wet surfaces), and have controlledpermeability. Polymeric films (which may be porous or non-porous) areparticularly useful for application to the surface of a device orimplant as well as to the surface of tissue, cavity or an organ.

Films may be made by several processes, including for example, bycasting, and by spraying, or may be formed at the treatment site insitu. For example, a sprayable formulation may be applied onto thetreatment site which then forms into a solid film.

In another aspect, the device may comprise or be in the form of a mesh.A mesh, as used herein, is a material composed of a plurality of fibersor filaments (i.e., a fibrous material), where the fibers or filamentsare arranged in such a manner (e.g., interwoven, knotted, braided,overlapping, looped, knitted, interlaced, intertwined, webbed, felted,and the like) so as to form a porous structure. Typically, a mesh is apliable material, such that it has sufficient flexibility to be wrappedaround a device. In certain aspects, the mesh may be sufficientlypliable so as to be capable of being wrapped around the external surfaceof a body passageway or cavity, or a portion thereof. The mesh may becapable of providing support to the structure (e.g., the vessel orcavity wall). In certain aspects, the mesh may be adapted to release anamount of the therapeutic agent.

Mesh materials may take a variety of forms. For example, the mesh may bein a woven, knit, or non-woven form and may include fibers or filamentsthat are randomly oriented relative to each other or that are arrangedin an ordered array or pattern. In one embodiment, for example, a meshmay be in the form of a fabric, such as, for example, a knitted,braided, crocheted, woven, non-woven (e.g., a melt-blown or wet-laid) orwebbed fabric. In one embodiment, a mesh may include a natural orsynthetic biodegradable polymer that may be formed into a knit mesh, aweave mesh, a sprayed mesh, a web mesh, a braided mesh, a looped mesh,and the like. Preferably, a mesh or wrap has intertwined threads thatform a porous structure, which may be, for example, knitted, woven, orwebbed.

The structure and properties of the mesh used in a device depend on theapplication and the desired mechanical (i.e., flexibility, tensilestrength, and elasticity), degradation properties, and the desiredloading and release characteristics for the selected therapeuticagent(s). The mesh should have mechanical properties, such that thedevice can remain sufficiently strong until the surrounding tissue hashealed. Factors that affect the flexibility and mechanical strength ofthe mesh include, for example, the porosity, fabric thickness, fiberdiameter, polymer composition (e.g., type of monomers and initiators),process conditions, and the additives that are used to prepare thematerial.

Typically, the mesh possesses sufficient porosity to permit the flow offluids through the pores of the fiber network and to facilitate tissueingrowth. Generally, the interstices of the mesh should be wide enoughapart to allow light visible by eye, or fluids, to pass through thepores. However, materials having a more compact structure also may beused. The flow of fluid through the interstices of the mesh may dependon a variety of factors, including, for example, the stitch count orthread density. The porosity of the mesh may be further tailored by, forexample, filling the interstices of the mesh with another material(e.g., particles or polymer) or by processing the mesh (e.g., byheating) in order to reduce the pore size and to create non-fibrousareas. Fluid flow through the mesh of the invention can vary dependingon the properties of the fluid, such as viscosity,hydrophilicity/hydrophobicity, ionic concentration, temperature,elasticity, pseudoplasticity, particulate content, and the like. Theinterstices of the mesh can be large enough so as to not prevent therelease of impregnated or coated therapeutic agent(s) from the mesh, andthe interstices preferably do not prevent the exchange of tissue fluidat the application site.

Mesh materials should be sufficiently flexible so as to be capable ofconforming to the shape of a device surface or an anatomotical surface.In certain cases, the mesh material may be sufficiently flexible so asto be capable of being wrapped around all or a portion of the externalsurface of a body passageway or cavity. Flexible mesh materials aretypically in the form of flexible woven or knitted sheets having athickness ranging from about 25 microns to about 3000 microns;preferably from about 50 to about 1000 microns. Mesh materials for usein the practice of the invention typically range from about 100 to 400microns in thickness.

The diameter and length of the fibers or filaments may range in sizedepending on the form of the material (e.g., knit, woven, or non-woven),and the desired elasticity, porosity, surface area, flexibility, andtensile strength. The fibers may be of any length, ranging from shortfilaments to long threads (i.e., several microns to hundreds of metersin length). Depending on the application, the fibers may have amonofilament or a multifilament construction.

The mesh may include fibers that are of same dimension or of differentdimensions, and the fibers may be formed from the same or differenttypes of biodegradable polymers. Woven materials, for example, mayinclude a regular or irregular array of warp and weft strands and mayinclude one type of polymer in the weft direction and another type(having the same or a different degradation profile from the firstpolymer) in the warp direction. The degradation profile of the weftpolymer may be different than or the same as the degradation profile ofthe warp polymer. Similarly, knit materials may include one or moretypes (e.g., monofilament, multi-filament) and sizes of fibers and mayinclude fibers made from the same or from different types ofbiodegradable polymers.

The structure of the mesh (e.g., fiber density and porosity) may impactthe amount of therapeutic agent that may be loaded into or onto thedevice. For example, a fabric having a loose weave characterized by alow fiber density and high porosity can have a lower thread count,resulting in a reduced total fiber volume and surface area. As a result,the amount of agent that may be loaded into or onto, with a fixedcarrier: therapeutic agent ratio, the fibers can be lower than for afabric having a high fiber density and lower porosity. It is generallypreferable that the mesh also should not invoke biologically detrimentalinflammatory or toxic response, should be capable of being fullymetabolized in the body, have an acceptable shelf life (of about atleast one year or more), and be easily sterilized.

The device may include multiple mesh materials in any combination orarrangement. For example, a portion of the device may be a knittedmaterial and another portion may be a woven material. In anotherembodiment, the device may more than one layer (e.g., a layer of wovenmaterial fused to a layer of knitted material or to another layer of thesame type or a different type of woven material). In some embodiments,multi-layer constructions (e.g., device having two or more layers ofmaterial) may be used, for example, to enhance the performanceproperties of the device (e.g. for enhancing the rigidity or foraltering the porosity, elasticity, or tensile strength of the device) orfor increasing the amount of drug loading.

The mesh or film may be formed of or include a polymer. The polymer maybe a biodegradable or a non-biodegradable polymer, or a combinationthereof.

Biodegradable compositions that may be used to prepare the mesh of filminclude polymers that comprise albumin, collagen, hyaluronic acid andderivatives, sodium alginate and derivatives, chitosan and derivativesgelatin, starch, cellulose polymers (for example methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, cellulose acetate phthalate, cellulose acetatesuccinate, hydroxypropylmethylcellulose phthalate), casein, dextran andderivatives, polysaccharides, poly(caprolactone), fibrinogen,poly(hydroxyl acids), poly(L-lactide) poly(D, L lactide), poly(D,L-lactide-co-glycolide), poly(L-lactide-co-glycolide), copolymers oflactic acid and glycolic acid, copolymers of ε-caprolactone and lactide,copolymers of glycolide and ε-caprolactone, copolymers of lactide and1,4-dioxane-2-one, polymers and copolymers that include one or more ofthe residue units of the monomers D-lactide, L-lactide, D,L-lactide,glycolide, ε-caprolactone, trimethylene carbonate, 1,4-dioxane-2-one or1,5-dioxepan-2-one, poly(glycolide), poly(hydroxybutyrate),poly(alkylcarbonate) and poly(orthoesters), polyesters,poly(hydroxyvaleric acid), polydioxanone, poly(ethylene terephthalate),poly(malic acid), poly(tartronic acid), polyanhydrides,polyphosphazenes, poly(amino acids). These compositions includecopolymers of the above polymers as well as blends and combinations ofthe above polymers. (see, generally, Illum, L., Davids, S. S. (eds.)“Polymers in Controlled Drug Delivery” Wright, Bristol, 1987; Arshady,J. Controlled Release 17: 1-22, 1991; Pitt, Int. J. Phar. 59: 173-196,1990; Holland et al., J. Controlled Release 4: 155-0180, 1986).

In one aspect, the mesh or film includes a biodegradable or resorbablepolymer that is formed from one or more monomers selected from the groupconsisting of lactide, glycolide, e-caprolactone, trimethylenecarbonate, 1,4-dioxan-2-one, 1,5-dioxepan-2-one, 1,4-dioxepan-2-one,hydroxyvalerate, and hydroxybutyrate. In one aspect, the polymer mayinclude, for example, a copolymer of a lactide and a glycolide. Inanother aspect, the polymer includes a poly(caprolactone). In yetanother aspect, the polymer includes a poly(lactic acid),poly(L-lactide)/poly(D,L-Lactide) blends or copolymers of L-lactide andD,L-lactide. In yet another aspect, the polymer includes a copolymer oflactide and e-caprolactone. In yet another aspect, the polymer includesa polyester (e.g., a poly(lactide-co-glycolide). Thepoly(lactide-co-glycolide) may have a lactide:glycolide ratio rangesfrom about 20:80 to about 2:98, a lactide:glycolide ratio of about10:90, or a lactide:glycolide ratio of about 5:95. In one aspect, thepoly(lactide-co-glycolide) is poly(L-lactide-co-glycolide). Otherexamples of biodegradable materials include polyglactin, polyglycolicacid, autogenous, heterogenous, and xenogeneic tissue (e.g., pericardiumor small intestine submucosa), and oxidized, regenerated cellulose.These meshes can be knitted, woven or non-woven meshes. Other examplesof non-woven meshes include electrospun materials.

Representative examples of non-biodegradable compositions for use informing films and meshes include ethylene-co-vinyl acetate copolymers,acrylic-based and methacrylic-based polymers (e.g., poly(acrylic acid),poly(methylacrylic acid), poly(methylmethacrylate),poly(hydroxyethylmethacrylate), poly(alkylcynoacrylate), poly(alkylacrylates), poly(alkyl methacrylates)), polyolefins such aspoly(ethylene) or poly(propylene), polyamides (e.g., nylon 6,6),poly(urethanes) (e.g. poly(ester urethanes), poly(ether urethanes),poly(carbonate urethanes), poly(ester-urea)), polyesters (e.g., PET,polybutyleneterephthalate, and polyhexyleneterephthalate), polyethers(poly(ethylene oxide), poly(propylene oxide), poly(ethyleneoxide)-poly(propylene oxide) copolymers, diblock and triblockcopolymers, poly(tetramethylene glycol)), silicone containing polymersand vinyl-based polymers (polyvinylpyrrolidone, poly(vinyl alcohol),poly(vinyl acetate phthalate), poly(styrene-co-isobutylene-co-styrene),fluorine containing polymers (fluoropolymers) such as fluorinatedethylene propylene (FEP) or polytetrafluoroethylene (e.g., expandedPTFE).

A variety of film mesh materials have been described which may becombined with a scarring agent. For example, the film or mesh may be abiodegradable polymeric matrix that conforms to the tissue and releasesthe agent in a controlled release manner. See e.g., U.S. Pat. No.6,461,640. The film or mesh may be a self-adhering silicone sheet whichis impregnated with an antioxidant and/or antimicrobial. See e.g., U.S.Pat. No. 6,572,878. The film or mesh may be a pliable shield withattachment ports and fenestrations that is adapted to cover a bonydissection in the spine. See e.g., U.S. Pat. No. 5,868,745 and U.S.Patent Application No. 2003/0078588. The film or mesh may be aresorbable micro-membrane having a single layer of non-porous polymerbase material of poly-lactide. See e.g., U.S. Pat. No. 6,531,146 andU.S. Application No. 2004/0137033. The film or mesh may be a wounddressing garment composed of an outer pliable layer and a self-adhesiveinner gel lining which serves as a dressing for contacting wounds. Seee.g., U.S. Pat. No. 6,548,728. The film or mesh may be a bandage with ascar treatment pad with a layer of silicone elastomer or silicone gel.See e.g., U.S. Pat. Nos. 6,284,941 and 5,891,076. The film or mesh maybe a crosslinkable system with at least three reactive compounds eachhaving a polymeric molecular core with at least one functional group.See e.g., U.S. Pat. No. 6,458,889. The film or mesh may be composed of aprosthetic fabric having a 3-dimensional structure separating twosurfaces in which one is open to post-surgical cell colonization and oneis linked to a film of collagenous material. See e.g., U.S. Pat. No.6,451,032. The film or mesh may be composed by crosslinking twosynthetic polymers, one having nucleophilic groups and the other havingelectrophilic groups, such that they form a matrix that may be used toincorporate a biologically active compound. See e.g., U.S. Pat. Nos.6,323,278; 6,166,130; 6,051,648 and 5,874,500. The film or mesh may be aconformable warp-knit fabric of oxidized regenerated cellulose or otherbioresorbable material which acts like a physical barrier to preventpostoperative adhesions. See e.g., U.S. Pat. No. 5,007,916. Meshes foruse in the practice of the invention also are described in U.S. Pat. No.6,575,887, and co-pending application, entitled “Perivascular Wraps,”filed Sep. 26, 2003 (U.S. Ser. No. (U.S. Ser. No. 10/673,046), which ishereby incorporated by reference in its entirety.

In one aspect, the fibrosing agent can be incorporated into abiodegradable or dissolvable film or mesh that is then applied to thetreatment site prior or post implantation of the prosthesis/implant.Exemplary materials for the manufacture of these films or meshes arehyaluronic acid (crosslinked or non-crosslinked), cellulose derivatives(e.g., hydroxypropyl cellulose), PLGA, collagen and crosslinkedpoly(ethylene glycol).

Films and meshes, which may be combined with one or more scarring agentsaccording to the present invention, include commercially availableproducts. Examples of films and meshes into which a fibrosis-inducingagent can be incorporated include INTERCEED (Johnson & Johnson, Inc.),PRECLUDE (W.L. Gore), and POLYACTIVE (poly(ether ester) multiblockcopolymers (Osteotech, Inc., Shrewsbury, N.J.), based on poly(ethyleneglycol) and poly(butylene terephthalate), and SURGICAL absorbablehemostat gauze-like sheet from Johnson & Johnson. Another mesh is aprosthetic polypropylene mesh with a bioresorbable coating calledSEPRAMESH Biosurgical Composite (Genzyme Corporation, Cambridge, Mass.).One side of the mesh is coated with a bioresorbable layer of sodiumhyaluronate and carboxymethylcellulose, providing a temporary physicalbarrier that separates the underlying tissue and organ surfaces from themesh. The other side of the mesh is uncoated, allowing for completetissue ingrowth similar to bare polypropylene mesh. In one embodiment,the fibrosis-inducing agent may be applied only to the uncoated side ofSEPRAMESH and not to the sodium hyaluronate/carboxymethylcellulosecoated side. Other films and meshes include: (a) BARD MARLEX mesh (C.R.Bard, Inc.), which is a very dense knitted fabric structure with lowporosity; (b) monofilament polypropylene mesh such as PROLENE availablefrom Ethicon, Inc. Somerville, N.J. (see, e.g., U.S. Pat. Nos. 5,634,931and 5,824,082)); (c) SURGISIS GOLD and SURGISIS IHM soft tissue graft(both from Cook Surgical, Inc.) which are devices specificallyconfigured for use to reinforce soft tissue in repair of inguinalhernias in open and laparoscopic procedures; (d) thin walledpolypropylene surgical meshes such as are available from Atrium MedicalCorporation (Hudson, N.H.) under the trade names PROLITE, PROLITE ULTRA,and LITEMESH; (e) COMPOSIX hernia mesh (C.R. Bard, Murray Hill, N.J.),which incorporates a mesh patch (the patch includes two layers of aninert synthetic mesh, generally made of polypropylene, and is describedin U.S. Pat. No. 6,280,453) that includes a filament to stiffen andmaintain the device in a flat configuration; (f) VISILEX mesh (from C.R.Bard, Inc.), which is a polypropylene mesh that is constructed withmonofilament polypropylene; (g) other meshes available from C.R. Bard,Inc. which include PERFIX Plug, KUGEL Hernia Patch, 3D MAX mesh, LHImesh, DULEX mesh, and the VENTRALEX Hernia Patch; and (h) other types ofpolypropylene monofilament hernia mesh and plug products include HERTRAmesh 1, 2, and 2A, HERMESH 3, 4 & 5 and HERNIAMESH plugs T1, T2, and T3from Herniamesh USA, Inc. (Great Neck, N.Y.).

Other examples of commercially available meshes which may be combinedwith fibrosing agents include the following. Boston ScientificCorporation sells the TRELEX NATURAL Mesh which is composed of a knittedpolypropylene material. Ethicon, Inc. makes the absorbable VICRYL(polyglactin 910) meshes (knitted and woven) and MERSILENE PolyesterFiber Mesh. Dow Corning Corporation (Midland, Mich.) sells a meshmaterial formed from silicone elastomer known as SILASTIC Rx MedicalGrade Sheeting (Platinum Cured). United States Surgical/Syneture(Norwalk, Conn.) sells a mesh made from absorbable polyglycolic acidunder the trade name DEXON Mesh Products. Membrana Accurel Systems(Germany) sells the CELGARD microporous polypropylene fiber andmembrane. Gynecare Worldwide, a division of Ethicon, Inc. sells a meshmaterial made from oxidized, regenerated cellulose known as INTERCEEDTC7.

Numerous types of meshes and films and polymers for use with meshes andfilms have been described above. Methods for incorporating the fibrosingcompositions onto or into the film or mesh include: (a) affixing(directly or indirectly) to the film or mesh a fibrosing composition(e.g., by either a spraying process or dipping process as describedabove, with or without a carrier), (b) incorporating or impregnatinginto the film or mesh a fibrosing composition (e.g., by either aspraying process or dipping process as described above, with or withouta carrier (c) by coating the film or mesh with a substance such as ahydrogel which can in turn absorb the fibrosing composition, (d)constructing the film or mesh itself or a portion of the film or meshwith a fibrosing composition, or (e) by covalently binding the fibrosingagent directly to the film or mesh surface or to a linker (smallmolecule or polymer) that is coated or attached to the film or meshsurface. For devices that are coated, the coating process can beperformed in such a manner as to (a) coat only one surface of the filmor mesh or (b) coat all or parts of both sides of the film or mesh.

The therapeutic agent(s) may be an integral part of the film or mesh(i.e., may reside within the fibers of the mesh). The fibrosisinhibiting agent can be incorporated directly into the film or mesh orit can be incorporated into a secondary carrier (polymeric ornon-polymeric), as described above, that is then incorporated into thefilm or mesh.

Alternatively, or in addition, the film or mesh may be coated with afibrosing agent or a composition that includes the fibrosing agent. Thecoating may take the form of a surface-adherent coating, mask, film,gel, foam, or mold.

A variety of polymeric compositions have been described that may be usedin conjunction with the films and meshes of the invention. Suchcompositions may be in the form of, for example, gels, sprays, liquids,and pastes, or may be polymerized from monomeric or prepolymericconstituents in situ. For example, the composition may be a polymerictissue coating which is formed by applying a polymerization initiator tothe tissue and then covering it with a water-soluble macromer that ispolymerizable using free radical initiators under the influence of UVlight. See e.g., U.S. Pat. Nos. 6,177,095 and 6,083,524. The compositionmay be an aqueous composition including a surfactant, pentoxifylline anda polyoxyalkylene polyether. See e.g., U.S. Pat. No. 6,399,624. Thecomposition may be a hydrogel-forming, self-solvating, absorbablepolyester copolymers capable of selective, segmental association intocompliant hydrogels mass upon contact with an aqueous environment. Seee.g., U.S. Pat. No. 5,612,052. The composition may be composed of fluentpre-polymeric material that is emitted to the tissue surface and thenexposed to activating energy in situ to initiate conversion of theapplied material to non-fluent polymeric form. See e.g., U.S. Pat. Nos.6,004,547 and 5,612,050. The composition may be composed of a gasmixture of oxygen present in a volume ratio of 1 to 20%. See e.g., U.S.Pat. No. 6,428,500. The composition may be composed of an anionicpolymer having an acid sulfate and sulfur content greater than 5% whichacts to inhibit monocyte or macrophage invasion. See e.g., U.S. Pat. No.6,417,173. The composition may be composed of a non-gellingpolyoxyalkylene composition with or without a therapeutic agent. Seee.g., U.S. Pat. No. 6,436,425. The composition may be coated onto tissuesurfaces and may be composed of an aqueous solution of a hydrophilic,polymeric material (e.g., polypeptides or polysaccharide) having greaterthan 50,000 molecular weight and a concentration range of 0.01% to 15%by weight. See e.g., U.S. Pat. No. 6,464,970.

Other representative examples of polymeric compositions which may becoated onto the film or mesh include poly(ethylene glycol)-basedsystems, hyaluronic acid and crosslinked hyaluronic acid compositions.These compositions can be applied as the final composition or they canbe applied as materials that form crosslinked gel in situ.

Other compositions that can be combined with scarring agents inconjunction with films and meshes, include, but are not limited to: (a)sprayable PEG-containing formulations such as COSEAL, SPRAYGEL,FOCALSEAL or DURASEAL; (b) hyaluronic acid-containing formulations suchas RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT,INTERGEL, (c) polymeric gels such as REPEL or FLOWGEL, (d) dextransulfate gels such as the ADCON range of products, and (e) lipid basedcompositions such as ADSURF (Brittania Pharmaceuticals).

Prior to implantation, the film or mesh may be trimmed or cut from asheet of bulk material to match the configuration of the widenedforamen, canal, or dissection region, or at a minimum, to overlay theexposed tissue area. The film or mesh may be bent or shaped to match theparticular configuration of the placement region. The film or mesh mayalso be rolled in a cuff shape or cylindrical shape and placed aroundthe exterior periphery of the desired tissue. The film or mesh may beprovided in a relatively large bulk sheet and then cut into shapes tomold the particular structure and surface topography of the tissue ordevice to be wrapped. Alternatively, the film or mesh may be pre-shapedinto one or more patterns for subsequent use. The films and meshes maybe typically rectangular in shape and be placed at the desired locationwithin the surgical site by direct surgical placement or by endoscopictechniques. The film or mesh may be secured into place by wrapping itonto itself (i.e., self-adhesive), or by securing it with sutures,staples, sealant, and the like. Alternatively, the film or mesh mayadhere readily to tissue and therefore, additional securing mechanismsmay not be required.

Within further aspects of the present invention, polymeric carriers areprovided which are adapted to contain and release a hydrophobicfibrosis-inducing compound, and/or the carrier containing thehydrophobic compound, in combination with a carbohydrate, protein orpolypeptide. Within certain embodiments, the polymeric carrier containsor comprises regions, pockets, or granules of one or more hydrophobiccompounds. For example, within one embodiment of the invention,hydrophobic compounds may be incorporated within a matrix which containsthe hydrophobic fibrosis-inducing compound, followed by incorporation ofthe matrix within the polymeric carrier. A variety of matrices can beutilized in this regard, including for example, carbohydrates andpolysaccharides such as starch, cellulose, dextran, methylcellulose,sodium alginate, heparin, chitosan and hyaluronic acid and proteins orpolypeptides such as albumin, collagen and gelatin. Within alternativeembodiments, hydrophobic compounds may be contained within a hydrophobiccore, and this core contained within a hydrophilic shell.

Within another aspect of the present invention, polymeric carriers canbe materials that are formed in situ. In one embodiment, the precursorscan be monomers or macromers that contain unsaturated groups which canbe polymerized or crosslinked. The monomers or macromers can then, forexample, be injected into the treatment area or onto the surface of thetreatment area and polymerized or crosslinked in situ using a radiationsource (e.g., visible or UV light) or a free radical system (e.g.,potassium persulfate and ascorbic acid or iron and hydrogen peroxide).The polymerization or crosslinking step can be performed immediatelyprior to, simultaneously to, or post injection of the reagents into thetreatment site. Representative examples of compositions that undergofree radical polymerization or crosslinking reactions are described inWO 01/44307, WO 01/68720, WO 02/072166, WO 03/043552, WO 93/17669, andWO 00/64977, U.S. Pat. Nos. 5,900,245; 6,051,248; 6,083,524; 6,177,095;6,201,065; 6,217,894; 6,639,014; 6,352,710; 6,410,645; 6,531,147;5,567,435; 5,986,043; and 6,602,975, and U.S. Patent ApplicationPublication Nos. 2002/012796, 2002/0127266, 2002/0151650, 2003/0104032,2002/0091229, and 2003/0059906.

In another embodiment, the reagents can undergo anelectrophilic-nucleophilic reaction to produce a crosslinked matrix.Polymers terminated with nucleophilic groups such as amine, sulfhydryl,hydroxyl, —PH₂ or CO—NH—NH₂ can be used as the nucleophilic reagents andpolymers terminated with electrophilic groups such as succinimidyl,carboxylic acid, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone,maleimide, —S—S—(C₅H₄N) or activated esters, such as are used in peptidesynthesis can be used as the electrophilic reagents. For example, a4-armed thiol derivatized poly(ethylene glycol) (e.g., pentaerythritolpoly(ethylene glycol)ether tetra-sulfhydryl) can be reacted with a 4armed NHS-derivatized polyethylene glycol (e.g., pentaerythritolpoly(ethylene glycol)ether tetra-succinimidyl glutarate) under basicconditions (pH>about 8). Representative examples of compositions thatundergo such electrophilic-nucleophilic crosslinking reactions aredescribed, for example, in U.S. Pat. Nos. 5,752,974; 5,807,581;5,874,500; 5,936,035; 6,051,648; 6,165,489; 6,312,725; 6,458,889;6,495,127; 6,534,591; 6,624,245; 6,566,406; 6,610,033; 6,632,457; U.S.Patent Application Publication No. 2003/0077272A1; and co-pending patentapplications entitled “Tissue Reactive Compounds and Compositions andUses Thereof” (U.S. Ser. No. 60/437,384, filed Dec. 30, 2002, and U.S.Ser. No. 60/44,924, filed Jan. 17, 2003) and “Drug Delivery from RapidGelling Polymer Composition” (U.S. Ser. No. 60/437,471, filed Dec. 30,2002, and U.S. Ser. No. 60/440,875, filed Jan. 17, 2003).

In another embodiment, the electrophilic- or nucleophilic-terminatedpolymers can further comprise a polymer that can enhance the mechanicaland/or adhesive properties of the in situ forming compositions. Thispolymer can be a degradable or non-degradable polymer. For example, thepolymer may be collagen or a collagen derivative, for example methylatedcollagen. An example of an in situ forming composition usespentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl] (4-armedthiol PEG), pentaerythritol poly(ethylene glycol)ethertetra-succinimidyl glutarate] (4-armed NHS PEG) and methylated collagenas the reactive reagents. This composition, when mixed with theappropriate buffers can produce a crosslinked hydrogel. (See, e.g., U.S.Pat. Nos. 5,874,500; 6,051,648; 6,166,130; 5,565,519 and 6,312,725).

In another embodiment, the in situ forming material polymer can be apolyester. Polyesters that can be used in in situ forming compositionsinclude poly(hydroxyesters). In another embodiment, the polyester cancomprise the residues of one or more of the monomers selected fromlactide, lactic acid, glycolide, glycolic acid, e-caprolactone,gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid,beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone,?-decanolactone, d-decanolactone, trimethylene carbonate,1,4-dioxane-2-one or 1,5-dioxepan-2-one. Representative examples ofthese types of compositions are described in U.S. Pat. Nos. 5,874,500;5,936,035; 6,312,725; 6,495,127 and PCT Publication Nos. WO 2004/028547.

In another embodiment, the electrophilic-terminated polymer can bepartially or completely replaced by a small molecule or oligomer thatcomprises an electrophilic group (e.g., disuccinimidyl glutarate).

In another embodiment, the nucleophilic-terminated polymer can bepartially or completely replaced by a small molecule or oligomer thatcomprises a nucleophilic group (e.g., dicysteine, dilysine, trilysine,etc.).

Other examples of in situ forming materials that can be used includethose based on the crosslinking of proteins (described in, for example,U.S. Pat. Nos. RE38158; 4,839,345; 5,514,379, 5,583,114; 6,310,036;6,458,147; 6,371,975; U.S. Patent Application Publication Nos.2004/0063613A1, 2002/0161399A1, and 2001/0018598A1, and PCT PublicationNos. WO 03/090683, WO 01/45761, WO 99/66964, and WO 96/03159) and thosebased on isocyanate or isothiocyanate capped polymers (see, e.g., PCTPublication No. WO 04/021983).

Other examples of in situ forming materials can include reagents thatcomprise one or more cyanoacrylate groups. These reagents can be used toprepare a poly(alkylcyanoacrylate) or poly(carboxyalkylcyanoacrylate)(e.g., poly(ethylcyanoacrylate), poly(butylcyanoacrylate),poly(isobutylcyanoacrylate), poly(hexylcyanoacrylate),poly(methoxypropylcyanoacrylate), and poly(octylcyanoacrylate)).

Examples of commercially available cyanoacrylates that can be usedinclude DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND,TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUIDPROTECTANT.

In another embodiment, the cyanoacrylate compositions can furthercomprise additives to stabilize the reagents or alter the rate ofreaction of the cyanoacrylate. For example, a trimethylene carbonatebased polymer or an oxalate polymer of poly(ethylene glycol) or aε-caprolactone based copolymer can be mixed with a2-alkoxyalkylcyanoacrylate (e.g., 2-methoxypropylcyanoacrylate).Representative examples of these compositions are described in U.S. Pat.Nos. 5,350,798 and 6,299,631.

In another embodiment, the cyanoacrylate composition can be prepared bycapping heterochain polymers with a cyanoacrylate group. Thecyanoacrylate-capped heterochain polymer preferably has at least twocyanoacrylate ester groups per chain. The heterochain polymer cancomprise an absorbable poly(ester), poly(ester-carbonate),poly(ether-carbonate) and poly(ether-ester). The poly(ether-ester)sdescribed in U.S. Pat. Nos. 5,653,992 and 5,714,159 can also be used asthe heterochain polymers. A triaxial poly(ε-caprolactone-co-trimethylenecarbonate) is an example of a poly(ester-carbonate) that can be used.The heterochain polymer may be a polyether. Examples of polyethers thatcan be used include poly(ethylene glycol), poly(propylene glycol) andblock copolymers of poly(ethylene glycol) and poly(propylene glycol)(e.g., PLURONICS group of polymers including but not limited to PLURONICF127 or F68). Representative examples of these compositions aredescribed in U.S. Pat. No. 6,699,940.

As described above, the fibrosing agent can be coated onto the entiredevice or a portion of the device using the polymeric coatings describedabove. This can be accomplished, for example, by dipping, spraying,electrospinning, painting or by vacuum deposition. In addition to thecoating compositions and methods described above, there are variousother coating compositions and methods that are known in the art.Representative examples of these coating compositions and methods aredescribed in U.S. Pat. Nos. 6,610,016; 6,358,557; 6,306,176; 6,110,483;6,106,473; 5,997,517; 5,800,412; 5,525,348; 5,331,027; 5,001,009;6,562,136; 6,406,754; 6,344,035; 6,254,921; 6,214,901; 6,077,698;6,603,040; 6,278,018; 6,238,799; 6,096,726; 5,766,158; 5,599,576;4,119,094; 4,100,309; 6,599,558; 6,369,168; 6,521,283; 6,497,916;6251964; 6,225,431; 6,087,462; 6,083,257; 5,739,237; 5,739,236;5,705,583; 5648442; 5645883; 5,556,710; 5,496,581; 4,689,386; 6,214,115;6,090,901; 6,599,448; 6,054,504; 4,987,182; 4,847,324; and 4,642,267,U.S. Patent Application Publication Nos. 2003/0129130; 2001/0026834;2003/0190420; 2001/0000785; 2003/0059631; 2003/0190405; 2002/0146581;2003/020399; 2003/0129130, 2001/0026834; 2003/0190420; 2001/0000785;2003/0059631; 2003/0190405; 2002/0146581; and 2003/020399, and PCTPublication Nos. WO 02/055121; WO 01/57048; WO 01/52915; and WO01/01957.

Within another aspect of the invention, the biologically active agentcan be delivered with a non-polymeric agent. Examples of non-polymericagents include sucrose derivatives (e.g., sucrose acetate isobutyrate,sucrose oleate), sterols such as cholesterol, stigmasterol,beta-sitosterol, and estradiol; cholesteryl esters such as cholesterylstearate; C₁₂-C₂₄ fatty acids such as lauric acid, myristic acid,palmitic acid, stearic acid, arachidic acid, behenic acid, andlignoceric acid; C₁₈-C₃₆ mono-, di- and triacylglycerides such asglyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate,glyceryl monodocosanoate, glyceryl monomyristate, glycerylmonodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryldimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryltrimyristate, glyceryl tridecenoate, glycerol tristearate and mixturesthereof; sucrose fatty acid esters such as sucrose distearate andsucrose palmitate; sorbitan fatty acid esters such as sorbitanmonostearate, sorbitan monopalmitate and sorbitan tristearate; C₁₆-C₁₈fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol,and cetostearyl alcohol; esters of fatty alcohols and fatty acids suchas cetyl palmitate and cetearyl palmitate; anhydrides of fatty acidssuch as stearic anhydride; phospholipids including phosphatidylcholine(lecithin), phosphatidylserine, phosphatidylethanolamine,phosphatidylinositol, and lysoderivatives thereof; sphingosine andderivatives thereof; spingomyelins such as stearyl, palmitoyl, andtricosanyl spingomyelins; ceramides such as stearyl and palmitoylceramides; glycosphingolipids; lanolin and lanolin alcohols, calciumphosphate, sintered and unscintered hydoxyapatite, zeolites; andcombinations and mixtures thereof.

Representative examples of patents relating to non-polymeric deliverysystems and their preparation include U.S. Pat. Nos. 5,736,152;5,888,533; 6,120,789; 5,968,542; and 5,747,058.

Other carriers that may likewise be utilized to contain and deliverfibrosis-inducing agents described herein include: hydroxypropylcyclodextrin (Cserhati and Hollo, Int. J. Pharm. 108: 69-75, 1994),liposomes (see, e.g., Sharma et al., Cancer Res. 53: 5877-5881, 1993;Sharma and Straubinger, Pharm. Res. 11(60): 889-896, 1994; WO 93/18751;U.S. Pat. No. 5,242,073), liposome/gel (WO 94/26254), nanocapsules(Bartoli et al., J. Microencapsulation 7(2): 191-197, 1990), micelles(Alkan-Onyuksel et al., Pharm. Res. 11(2): 206-212, 1994), nanoparticles(Violante and Lanzafame PMCR), nanoparticles—modified (U.S. Pat. No.5,145,684), nanoparticles (surface modified) (U.S. Pat. No. 5,399,363),micelle (surfactant) (U.S. Pat. No. 5,403,858), synthetic phospholipidcompounds (U.S. Pat. No. 4,534,899), gas borne dispersion (U.S. Pat. No.5,301,664), liquid emulsions, foam, spray, gel, lotion, cream, ointment,dispersed vesicles, particles or droplets solid- or liquid-aerosols,microemulsions (U.S. Pat. No. 5,330,756), polymeric shell (nano- andmicro-capsule) (U.S. Pat. No. 5,439,686), emulsions (Tarr et al., PharmRes. 4: 62-165, 1987), nanospheres (Hagan et al., Proc. Intern. Symp.Control Rel. Bioact. Mater. 22, 1995; Kwon et al., Pharm Res. 12(2):192-195; Kwon et al., Pharm Res. 10(7): 970-974; Yokoyama et al., J.Contr. Rel. 32: 269-277, 1994; Gref et al., Science 263: 1600-1603,1994; Bazile et al., J. Pharm. Sci. 84: 493-498, 1994) and implants(U.S. Pat. No. 4,882,168, Jampel et al., Invest Ophthalm. Vis. Science34(11): 3076-3083, 1993; Walter et al., Cancer Res. 54: 22017-2212,1994).

In another embodiment, the fibrosis inducing agent can be incorporatedinto a composition that enhances osteointegration and/or osteogenesis.Examples of these compositions include materials composed ofbeta-tricalcium phosphate (e.g., VITOSS, PROOSTEON 500R), hydroxyapatiteor Ca₁₀(PO₄)₆OH (e.g., OSTEOGRAF, calcium carbonate or CaCO₃, calciumsulfate (e.g., OSTEOSET and ALLOMATRIX), calcium phosphate (e.g.,CALCIBON or NORIAN SRS) as well as synthetic bone fillers (e.g.,CORTOSS) and processed bone fillers (e.g., BIOOSS). Representativeexamples of these materials are described in U.S. Pat. Nos. 3,929,971,4,861,733; 6,527,810; 4,772,468; 4,882,149; 5,167,961; 6,576,015;4,839,215; 5,614,206; 5,807,567; 6,030,636; 6,652,887; 6,206,957;6,485,754; 4,347,234; 4,291,013; 5,129,905; 5,336,264; 5,569,442;5,571,493; 5,683,667; 5,709,742; 5,820,632; 5,658,332; 5,681,872;5,914,356; 5,939,039; 6,325,987; 6,383,519; 6,458,162; 6,736,799;6,521,246; and 6,709,744.

Within another aspect of the invention, the fibrosis-inducing agent canfurther comprise a secondary carrier. The secondary carrier can be inthe form of microspheres (e.g., PLGA, PLLA, PDLLA, PCL, gelatin,polydioxanone, poly(alkylcyanoacrylate)), nanospheres (e.g., PLGA, PLLA,PDLLA, PCL, gelatin, polydioxanone, poly(alkylcyanoacrylate)),liposomes, emulsions, microemulsions, micelles (e.g., SDS, blockcopolymers of the form X—Y, X—Y—X or Y—X—Y, where X is a poly(alkyleneoxide) or an alkyl ether thereof and Y is a polyester (e.g., PLGA, PLLA,PDLLA, PCL, polydioxanone)), zeolites or cyclodextrins.

Within another aspect of the invention, these fibrosis-inducingagent/secondary carrier compositions can be a) incorporated directlyinto or onto the device, b) incorporated into a solution, c)incorporated into a gel or viscous solution, d) incorporated into thecomposition used for coating the device, or e) incorporated into or ontothe device following coating of the device with a coating composition.

For example, fibrosis-inducing agent loaded PLGA microspheres may beincorporated into a polyurethane coating solution which is then coatedonto the device.

In yet another example, the device can be coated with a polyurethane andthen allowed to partially dry such that the surface is still tacky. Aparticulate form of the fibrosis-inducing agent or fibrosis-inducingagent/secondary carrier can then be applied to all or a portion of thetacky coating after which the device is dried.

In yet another example, the device can be coated with one of thecoatings described above. A thermal treatment process can then be usedto soften the coating, after which the fibrosis-inducing agent or thefibrosis-inducing agent/secondary carrier is applied to the entiredevice or to a portion of the device (e.g., outer surface).

Within another aspect of the invention, a coated device which inhibitsor reduces an in vivo fibrotic reaction is further coated with acompound or composition which delays the release of and/or activity ofthe fibrosis-inducing agent. Representative examples of such agentsinclude biologically inert materials such as gelatin, PLGA/MePEG film,PLA, polyurethanes, silicone rubbers, surfactants, lipids, orpolyethylene glycol, as well as biologically active materials such asheparin (e.g., to induce coagulation).

For example, in one embodiment of the invention, the active agent on thedevice is top-coated with a physical barrier. Such barriers can includenon-degradable materials or biodegradable materials such as gelatin,PLGA/MePEG film, PLA, polyethylene glycol, or the like. In oneembodiment, the rate of diffusion of the therapeutic agent in thebarrier coat is slower that the rate of diffusion of the therapeuticagent in the coating layer. In the case of PLGA/MePEG, once thePLGA/MePEG becomes exposed to the bloodstream, the MePEG can dissolveout of the PLGA, leaving channels through the PLGA to an underlyinglayer containing the fibrosis-inducing agent (e.g., silk or cyclosporineA), which can then diffuse into the vessel wall and initiate itsbiological activity.

In another embodiment of the invention, for example, a particulate formof the active agent (e.g., silk or cyclosporine A) may be coated ontothe device using a polymer (e.g., PLG, PLA, or polyurethane). A secondpolymer, that dissolves slowly or degrades (e.g., MePEG-PLGA or PLG) andthat does not contain the active agent, may be coated over the firstlayer. Once the top layer dissolves or degrades, it exposes the undercoating, which allows the active agent to be exposed to the treatmentsite or to be released from the coating.

Within another aspect of the invention, the outer layer of the coateddevice, which induces an in vivo fibrotic response, is further treatedto crosslink the outer layer of the coating. This can be accomplished bysubjecting the coated device to a plasma treatment process. The degreeof crosslinking and nature of the surface modification can be altered bychanging the RF power setting, the location with respect to the plasma,the duration of treatment as well as the gas composition introduced intothe plasma chamber.

Protection of a biologically active surface can also be utilized bycoating the device or implant surface with an inert molecule thatprevents access to the active site through steric hindrance, or bycoating the surface with an inactive form of the fibrosis-inducingagent, which is later activated. For example, the device can be coatedwith an enzyme, which causes either release of the fibrosis-inducingagent or activates the fibrosis-inducing agent.

Another example of a suitable device surface coating includes ananti-coagulant such as heparin, which can be coated on top of thefibrosis-inducing agent such that the presence of the heparin or otheranti-coagulant delays coagulation at the treatment site. As the heparinor other anticoagulant dissolves away, the anticoagulant activity mayslow or stop, and the newly exposed fibrosis-inducing agent (e.g., silkor cyclosporine A) is capable of inhibiting or reducing fibrosis fromoccurring in the adjacent tissue.

In another strategy, the device can be coated with an inactive form ofthe fibrosis-inducing agent, which is then activated once the device isdeployed. Such activation may be achieved by injecting another materialinto the treatment area after the device (as described below) isdeployed or after the fibrosis-inducing agent has been administered tothe treatment area (via, e.g., injections, spray, wash, drug deliverycatheters or balloons). For example, the device may be coated with aninactive form of the fibrosis-inducing agent. Once the device isdeployed, the activating substance is injected or applied into or ontothe treatment site where the inactive form of the fibrosis-inducingagent has been applied.

For example, a device may be coated with a biologically activefibrosis-inducing agent, in the usual manner. The coating containing theactive fibrosis-inducing agent may then be covered (e.g., coated) withpolyethylene glycol. The PEG and the fibrosing agent containing coatingmay be bonded through the formulation of a bond between reactive groupson the two layers. For example, an ester bond may be formed using acondensation reaction. Prior to the deployment of the device, anesterase is injected into the treatment site around the outside of theimplanted device. The esterase can cleave the bond between the ester andthe fibrosis-inducing agent, thereby allowing the agent to initiatefibrosis.

In another aspect, a medical device may include a plurality ofreservoirs within its structure, each reservoir configured to house andprotect a therapeutic drug. The reservoirs may be formed from divets inthe device surface or micropores or channels in the device body. In oneaspect, the reservoirs are formed from voids in the structure of thedevice. The reservoirs may house a single type of drug or more than onetype of drug. The druG(s) may be formulated with a carrier (e.g., apolymeric or non-polymeric material) that is loaded into the reservoirs.The filled reservoir can function as a drug delivery depot which canrelease drug over a period of time dependent on the release kinetics ofthe drug from the carrier. In certain embodiments, the reservoir may beloaded with a plurality of layers. Each layer may include a differentdrug having a particular amount (dose) of drug, and each layer may havea different composition to further tailor the amount of drug that isreleased from the substrate. The multi-layered carrier may furtherinclude a barrier layer that prevents release of the druG(s). Thebarrier layer can be used, for example, to control the direction thatthe drug elutes from the void.

Within certain embodiments of the invention, the therapeuticcompositions may also comprise additional ingredients such assurfactants (e.g., PLURONICS, such as F-127, L-122, L-101, L-92, L-81,and L-61), anti-inflammatory agents, anti-thrombotic agents,anti-infective agents, preservatives, anti-oxidants and/or anti-plateletagents.

Within certain embodiments of the invention, the therapeutic agent orcarrier can also comprise radio-opaque, echogenic materials and magneticresonance imaging (MRI) responsive materials (i.e., MRI contrast agents)to aid in visualization of the device under ultrasound, fluoroscopyand/or MRI. For example, a device may be made with or coated with acomposition which is echogenic or radiopaque (e.g., made with echogenicor radiopaque with materials such as powdered tantalum, tungsten, bariumcarbonate, bismuth oxide, barium sulfate, metrazimide, iopamidol,iohexol, iopromide, iobitridol, iomeprol, iopentol, ioversol, ioxilan,iodixanol, iotrolan, acetrizoic acid derivatives, diatrizoic acidderivatives, iothalamic acid derivatives, ioxithalamic acid derivatives,metrizoic acid derivatives, iodamide, lypophylic agents, iodipamide andioglycamic Acid or, by the addition of microspheres or bubbles whichpresent an acoustic interface). Visualization of a device by ultrasonicimaging may be achieved using an echogenic coating. Echogenic coatingsare described in, e.g., U.S. Pat. Nos. 6,106,473 and 6,610,016. Forvisualization under MRI, contrast agents (e.g., gadolinium (III)chelates or iron oxide compounds) may be incorporated into or onto thedevice, such as, as a component in a coating or within the void volumeof the device (e.g., within a lumen, reservoir, or within the structuralmaterial used to form the device). In some embodiments, a medical devicemay include radio-opaque or MRI visible markers (e.g., bands) that maybe used to orient and guide the device during the implantationprocedure.

Medical implants may, alternatively, or in addition, be visualized undervisible light, using fluorescence, or by other spectroscopic means.Visualization agents that can be included for this purpose include dyes,pigments, and other colored agents. In one aspect, the medical implantmay further include a colorant to improve visualization of the implantin vivo and/or ex vivo. Frequently, implants can be difficult tovisualize upon insertion, especially at the margins of implant. Acoloring agent can be incorporated into a medical implant to reduce oreliminate the incidence or severity of this problem. The coloring agentprovides a unique color, increased contrast, or unique fluorescencecharacteristics to the device. In one aspect, a solid implant isprovided that includes a colorant such that it is readily visible (undervisible light or using a fluorescence technique) and easilydifferentiated from its implant site. In another aspect, a colorant canbe included in a liquid or semi-solid composition. For example, a singlecomponent of a two component mixture may be colored, such that whencombined ex-vivo or in-vivo, the mixture is sufficiently colored.

The coloring agent may be, for example, an endogenous compound (e.g., anamino acid or vitamin) or a nutrient or food material and may be ahydrophobic or a hydrophilic compound. Preferably, the colorant has avery low or no toxicity at the concentration used. Also preferred arecolorants that are safe and normally enter the body through absorptionsuch as β-carotene. Representative examples of colored nutrients (undervisible light) include fat soluble vitamins such as Vitamin A (yellow);water soluble vitamins such as Vitamin B12 (pink-red) and folic acid(yellow-orange); carotenoids such as β-carotene (yellow-purple) andlycopene (red). Other examples of coloring agents include naturalproduct (berry and fruit) extracts such as anthrocyanin (purple) andsaffron extract (dark red). The coloring agent may be a fluorescent orphosphorescent compound such as α-tocopherolquinol (a Vitamin Ederivative) or L-tryptophan. Derivatives, analogues, and isomers of anyof the above colored compounds also may be used. The method forincorporating a colorant into an implant or therapeutic composition maybe varied depending on the properties of and the desired location forthe colorant. For example, a hydrophobic colorant may be selected forhydrophobic matrices. The colorant may be incorporated into a carriermatrix, such as micelles. Further, the pH of the environment may becontrolled to further control the color and intensity.

In one aspect, the composition of the present invention include one ormore coloring agents, also referred to as dyestuffs, which will bepresent in an effective amount to impart observable coloration to thecomposition, e.g., the gel. Examples of coloring agents include dyessuitable for food such as those known as F. D. & C. dyes and naturalcoloring agents such as grape skin extract, beet red powder, betacarotene, annato, carmine, turmeric, paprika, and so forth. Derivatives,analogues, and isomers of any of the above colored compound also may beused. The method for incorporating a colorant into an implant ortherapeutic composition may be varied depending on the properties of andthe desired location for the colorant. For example, a hydrophobiccolorant may be selected for hydrophobic matrices. The colorant may beincorporated into a carrier matrix, such as micelles. Further, the pH ofthe environment may be controlled to further control the color andintensity.

In one aspect, the compositions of the present invention include one ormore preservatives or bacteriostatic agents, present in an effectiveamount to preserve the composition and/or inhibit bacterial growth inthe composition, for example, bismuth tribromophenate, methylhydroxybenzoate, bacitracin, ethyl hydroxybenzoate, propylhydroxybenzoate, erythromycin, chlorocresol, benzalkonium chlorides, andthe like. Additional examples of the preservative include paraoxybenzoicacid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol,dehydroacetic acid, sorbic acid, and the like. In one aspect, thecompositions of the present invention include one or more bactericidal(also known as bacteriacidal) agents.

In one aspect, the compositions of the present invention include one ormore antioxidants, present in an effective amount. Examples of theantioxidant include sulfites, alpha-tocopherol and ascorbic acid.

Within related aspects of the present invention, devices andcompositions are provided that may or may not be associated with adevice, which release an agent which induces fibrosis in vivo upondeployment of the device or administration of the composition. Incertain aspects, the fibrosis-inducing agent or composition thatcomprises the fibrosis-inducing agent is delivered locally or regionallyto the treatment site from the device or composition.

Within certain aspects of the present invention, the therapeuticcomposition should be biocompatible, and release one or more fibrosingagents over a period of several hours, days, or months.

The devices of the present invention may be configured to release thescarring agent at one or more phases, the one or more phases havingsimilar or different performance (e.g., release) profiles. Thetherapeutic agent may be made available to the tissue at amounts whichmay be sustainable, intermittent, or continuous; in one or more phases;and/or rates of delivery; effective to increase or promote any one ormore components of fibrosis (or scarring), including: formation of newblood vessels (angiogenesis), migration and proliferation of connectivetissue cells (such as fibroblasts or smooth muscle cells), deposition ofextracellular matrix (ECM), and remodeling (maturation and organizationof the fibrous tissue); or the agent can act as a vascular wallirritant.

Thus, the release rate may be programmed to impact fibrosis (orscarring) by releasing the scarring agent at a time such that at leastone of the components of fibrosis is promoted or increased. Moreover,the predetermined release rate may reduce agent loading and/orconcentration as well as potentially providing minimal drug washout andthus, increases efficiency of drug effect. Any one of at least onescarring agent(s) may perform one or more functions, including promotingthe formation of new blood vessels (angiogenesis), promoting themigration and proliferation of connective tissue cells (such asfibroblasts or smooth muscle cells), promoting the deposition ofextracellular matrix (ECM), promoting remodeling (maturation andorganization of the fibrous tissue) and/or acting as a vascular wallirritant. In one embodiment, the rate of release may provide asustainable level of the scarring agent to the treatment site. Inanother embodiment, the rate of release is substantially constant. Therate may decrease and/or increase over time, and it may optionallyinclude a substantially non-release period. The release rate maycomprise a plurality of rates. In an embodiment, the plurality ofrelease rates may include rates selected from the group consisting ofsubstantially constant, decreasing, increasing, and substantiallynon-releasing.

The total amount of scarring agent made available on, in or near thedevice may be in an amount ranging from about 0.01 μg (micrograms) toabout 2500 mg (milligrams). Generally, the scarring agent may be in theamount ranging from 0.01 μg to about 10 μg; or from 10 μg to about 1 mg;or from 1 mg to about 10 mg; or from 10 mg to about 100 mg; or from 100mg to about 500 mg; or from 500 mg to about 2500 mg.

The surface amount of scarring agent on, in or near the device may be inan amount ranging from less than 0.01 μg to about 250 μg per mm² ofdevice surface area. Generally, the scarring agent may be in the amountranging from less than 0.01 μg/mm²; or from 0.01 μg to about 10 μg/mm²;or from 10 μg to about 25 μg/mm²; or from 25 μg to about 250 μg/mm².

The scarring agent that is on, in or near the device may be releasedfrom the composition and/or device in a time period that may be measuredfrom the time of implantation, which ranges from about less than 1 dayto about 180 days. Generally, the release time may also be from aboutless than 1 day to about 7 days; from 7 days to about 14 days; from 14days to about 28 days; from 28 days to about 56 days; from 56 days toabout 90 days; from 90 days to about 180 days.

In one aspect, “quick release” or “burst” therapeutic compositions areprovided that release greater than 10%, 20%, or 25% (w/v) of afibrosis-inducing agent over a period of 7 to 10 days. Such “quickrelease” compositions should, within certain embodiments, be capable ofreleasing therapeutic levels (where applicable) of a desired fibrosingagent. Within other embodiments, “slow release” therapeutic compositionsare provided that release less than 1% (w/v) of a fibrosis-inducingagent over a period of 7 to 10 days. Within other embodimentstherapeutic compositions are provided that release either less than 1%(w/v) of a fibrosing-inducing agent over a period longer than 10 days ordo not release the therapeutic composition at all, but maintain thecomposition for a very long period of time such as for the entireduration of the device placement in the body.

The amount of scarring agent released from the composition and/or deviceas a function of time may be determined based on the in vitro releasecharacteristics of the agent from the composition. The in vitro releaserate may be determined by placing the scarring agent within thecomposition or device in an appropriate buffer such as 0.1M phosphatebuffer (pH 7.4)) at 37° C. Samples of the buffer solution are thenperiodically removed for analysis by either HPLC or by gravimetricmeans, and the buffer is replaced to avoid any saturation effects.

Based on the in vitro release rates, the release of scarring agent perday may range from an amount ranging from about 0.0 μg (micrograms) toabout 2500 mg (milligrams). Generally, the scarring agent that may bereleased in a day may be in the amount ranging from 0.0 to 0.01 μg; 0.01μg to about 10 μg; or from 10 μg to about 1 mg; or from 1 mg to about 10mg; or from 10 mg to about 100 mg; or from 100 mg to about 500 mg; orfrom 500 mg to about 2500 mg. In one embodiment, the scarring agent ismade available to the susceptible tissue site in a constant butsubstantially unchanging manner so that the agent remains at the tissueessentially permanently. In another embodiment, the scarring agent ismade available to the susceptible tissue in a sustained and/orcontrolled manner which results in increased efficiency and/or efficacy.Further, the release rates may vary during either or both of the initialand subsequent release phases. There may also be additional phase(s) forrelease of the same substance(s) and/or different substance(s).

Further, therapeutic compositions of the present invention shouldpreferably be have a stable shelf-life for at least several months andcapable of being produced and maintained under sterile conditions. Thecomposition may be sterile either by preparing them under asepticenvironment and/or they may be terminally sterilized using methodsavailable in the art. Many pharmaceuticals are manufactured to besterile and this criterion is defined by the USP XXII <1211>. The term“USP” refers to U.S. Pharmacopeia (see www.usp.org, Rockville, Md.).Sterilization may be accomplished by a number of means accepted in theindustry and listed in the USP XXII <1211>, including gas sterilization,ionizing radiation or, when appropriate, filtration. Sterilization maybe maintained by what is termed asceptic processing, defined also in USPXXII >1211>. Acceptable gases used for gas sterilization includeethylene oxide. Acceptable radiation types used for ionizing radiationmethods include gamma, for instance from a cobalt 60 source and electronbeam. A typical dose of gamma radiation is 2.5 MRad. Sterilization mayalso occur by terminally using gamma radiation or electron beamsterilization methods. Filtration may be accomplished using a filterwith suitable pore size, for example 0.22 μm and of a suitable material,for instance polytetrafluoroethylene (e.g., TEFLON). A combination ofthese methods may also be used to prepare the composition in the sterileform.

In another aspect, the compositions and devices of the present inventionare contained in a container that allows them to be used for theirintended purpose. Properties of the container that are important are avolume of empty space to allow for the addition of a constitutionmedium, such as water or other aqueous medium, e.g., saline, acceptablelight transmission characteristics in order to prevent light energy fromdamaging the composition in the container (refer to USP XXII <661>), anacceptable limit of extractables within the container material (refer toUSP XXII), an acceptable barrier capacity for moisture (refer to USPXXII <671>) or oxygen. In the case of oxygen penetration, this may becontrolled by including in the container, a positive pressure of aninert gas, such as high purity nitrogen, or a noble gas, such as argon.

Typical materials used to make containers for pharmaceuticals includeUSP Type I through III and Type NP glass (refer to USP XXII <661>),polyethylene, TEFLON, silicone, and gray-butyl rubber. For parenterals,USP Types I to III glass and polyethylene are preferred.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

For all the previously described embodiments, examples of suitablefibrosing agents include tissue irritants such tissue as silk, wool,asbestos, silica, bleomycin, neomycin, talcum powder, metallicberyllium, and copper are particularly suitable for the practice of thisinvention. Other agents which may be incorporated into or onto theimplant or device or released from the implant or device includeextracellular matrix components such as fibrous structural proteins(e.g., fibrillar collagens, nonfibrillar collagen and elastins),adhesive glycoproteins (e.g., laminin and fibronectin), proteoglycans(e.g., heparin sulphate, chondroitin sulphate, dermatan sulphate),hyaluronan (e.g., hyaluronic acid), secreted protein acidic and rich incysteine (SPARC), thrombospondins, tenacin, inhibitors of matrixmetalloproteinases (e.g., TIMPs and synthetic TIMPs such as marimistat,batimistat, doxycycline, tetracycline, minocycline, TROCADE, Ro-1130830,CGS 27023A, BMS-275291) and polylysine. Growth factors and inflammatorycytokines involved in angiogenesis, fibroblast migration, fibroblastproliferation, ECM synthesis and tissue remodeling such as epidermalgrowth factor (EGF) family, transforming growth factor-α (TGF-α),transforming growth factor-β (TGF-9-1, TGF-9-2, TGF-9-3),platelet-derived growth factor (PDGF), fibroblast growth factor(acidic—aFGF; and basic—bFGF), bone morphogenic proteins, activins,vascular endothelial growth factor (VEGF, VEGF-B, VEGF-C, placentalgrowth factor—PIGF), angiopoietins, insulin-like growth factors (IGF),hepatocyte hrowth factor (HGF), connective tissue growth factor (CTGF),myeloid colony-stimulating factors (CSFs), granulocyte-macrophagecolony-stimulating factors (GM-CSF), granulocyte colony-stimulatingfactor (G-CSF), macrophage colony-stimulating factor (M-CSF),erythropoietin, interleukins (particularly IL-1, IL-8, IL-6), tumornecrosis factor-α (TNF9), nerve growth factor (NGF), interferon-α,interferon-β, and growth hormone (GH) are also suitable forincorporation and release from specific intravascular devices. Otheragents which may be coated onto or released by the implant or deviceinclude adhesives such as cyanoacrylate or materials made from 4-armedthiol PEG (10K), a 4-armed NHS PEG(10K) and methylated collagen.

5) Coating of Devices with Fibrosis-Inducing Agents

As described above, a range of polymeric and non-polymeric materials canbe used to incorporate the fibrosis-inducing agent onto or into adevice. Coating of the device with these fibrosis-inducing agentcontaining compositions or with the fibrosis-inducing agent only is oneprocess that can be used to incorporate the fibrosis-inducing agent intoor onto the device.

a) Dip Coating

Dip coating is an example of a coating process that can be used toassociate the fibrosis-inducing agent with the device. In oneembodiment, the fibrosis-inducing agent is dissolved in a solvent forthe fibrosis agent and is then coated onto the device.

Fibrosis-Inducing Agent with an Inert Solvent

In one embodiment, the solvent is an inert solvent for the device suchthat the solvent does not dissolve the medical device to any greatextent and is not absorbed by the device to any great extent. The devicecan be immersed, either partially or completely, in thefibrosis-inducing agent/solvent solution for a specific period of time.The rate of immersion into the fibrosis-inducing agent/solvent solutioncan be altered (e.g., 0.001 cm per sec to 50 cm per sec). The device canthen be removed from the solution. The rate at which the device can bewithdrawn from the solution can be altered (e.g., 0.001 cm per sec to 50cm per sec). The coated device can be air-dried. The dipping process canbe repeated one or more times depending on the specific application. Thedevice can be dried under vacuum to reduce residual solvent levels. Thisprocess can result in the fibrosis-inducing agent being coated on thesurface of the device.

Fibrosis-Inducing Agent with a Swelling Solvent

In one embodiment, the solvent is one that can not dissolve the devicebut can be absorbed by the device. These solvents can thus swell thedevice to some extent. The device can be immersed, either partially orcompletely, in the fibrosis-inducing agent/solvent solution for aspecific period of time (seconds to days). The rate of immersion intothe fibrosis-inducing agent/solvent solution can be altered (e.g., 0.001cm per sec to 50 cm per sec). The device can then be removed from thesolution. The rate at which the device can be withdrawn from thesolution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). Thecoated device can be air-dried. The dipping process can be repeated oneor more times depending on the specific application. The device can bedried under vacuum to reduce residual solvent levels. This process canresult in the fibrosis-inducing agent being adsorbed into the medicaldevice. The fibrosis-inducing agent may also be present on the surfaceof the device. The amount of surface associated fibrosis-inducing agentmay be reduced by dipping the coated device into a solvent for thefibrosis-inducing agent or by spraying the coated device with a solventfor the fibrosis-inducing agent.

Fibrosis-Inducing Agent with a Solvent

In one embodiment, the solvent is one that can be absorbed by the deviceand that can dissolve the device. The device can be immersed, eitherpartially or completely, in the fibrosis-inducing agent/solvent solutionfor a specific period of time (seconds to hours). The rate of immersioninto the fibrosis-inducing agent/solvent solution can be altered (e.g.,0.001 cm per sec to 50 cm per sec). The device can then be removed fromthe solution. The rate at which the device can be withdrawn from thesolution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). Thecoated device can be air-dried. The dipping process can be repeated oneor more times depending on the specific application. The device can bedried under vacuum to reduce residual solvent levels. This process canresult in the fibrosis-inducing agent being adsorbed into the medicaldevice as well as being surface associated. Preferably, the exposuretime of the device to the solvent may be such as to not incursignificant permanent dimensional changes to the device. Thefibrosis-inducing agent may also be present on the surface of thedevice. The amount of surface associated fibrosis-inducing agent may bereduced by dipping the coated device into a solvent for thefibrosis-inducing agent or by spraying the coated device with a solventfor the fibrosis-inducing agent.

In one embodiment, the fibrosis-inducing agent and a polymer aredissolved in a solvent, for both the polymer and the fibrosing agent,and are then coated onto the device.

In the above description, the device can be a device that has not beenmodified or device that has been further modified by coating with apolymer, surface treated by plasma treatment, flame treatment, coronatreatment, surface oxidation or reduction, surface etching, mechanicalsmoothing or roughening, or grafting prior to the coating process.

In any one of the above dip coating methods, the surface of the devicecan be treated with a plasma polymerization method prior to coating ofthe scarring agent or scarring agent containing composition, such that athin polymeric layer is deposited onto the device surface. Examples ofsuch methods include parylene coating of devices and the use of variousmonomers such hydrocyclosiloxane monomers. Parylene coating may beespecially advantageous if the device, or portions of the device, arecomposed of materials (e.g., stainless steel, nitinol) that do not allowincorporation of the therapeutic agent(s) into the surface layer usingone of the above methods. A parylene primer layer may be deposited ontothe device using a parylene coater (e.g., PDS 2010 LABCOTER2 fromCookson Electronics) and a suitable reagent (e.g., di-p-xylylene ordichloro-di-p-xylylene) as the coating feed material. Parylene compoundsare commercially available, for example, from Specialty Coating Systems,Indianapolis, Ind.), including PARYLENE N (di-p-xylylene), PARYLENE C (amonchlorinated derivative of PARYLENE N, and PARYLENE D, a dichlorinatedderivative of Parylene N.J.).

Fibrosis-Inducing Agent/Polymer with an Inert Solvent

In one embodiment, the solvent is an inert solvent for the device suchthat the solvent does not dissolve the medical device to any greatextent and is not absorbed by the device to any great extent. The devicecan be immersed, either partially or completely, in thefibrosis-inducing agent/polymer/solvent solution for a specific periodof time. The rate of immersion into the fibrosis-inducingagent/polymer/solvent solution can be altered (e.g., 0.001 cm per sec to50 cm per sec). The device can then be removed from the solution. Therate at which the device can be withdrawn from the solution can bealtered (e.g., 0.001 cm per sec to 50 cm per sec). The coated device canbe air-dried. The dipping process can be repeated one or more timesdepending on the specific application. The device can be dried undervacuum to reduce residual solvent levels. This process can result in thefibrosis-inducing agent/polymer being coated on the surface of thedevice.

Fibrosis-Inducing Agent/Polymer with a Swelling Solvent

In one embodiment, the solvent is one that can not dissolve the devicebut can be absorbed by the device. These solvents can thus swell thedevice to some extent. The device can be immersed, either partially orcompletely, in the fibrosis-inducing agent/polymer/solvent solution fora specific period of time (seconds to days). The rate of immersion intothe fibrosis-inducing agent/polymer/solvent solution can be altered(e.g., 0.001 cm per sec to 50 cm per sec). The device can then beremoved from the solution. The rate at which the device can be withdrawnfrom the solution can be altered (e.g., 0.001 cm per sec to 50 cm persec). The coated device can be air-dried. The dipping process can berepeated one or more times depending on the specific application. Thedevice can be dried under vacuum to reduce residual solvent levels. Thisprocess can result in the fibrosis-inducing agent/polymer being coatedonto the surface of the device as well as the potential for thefibrosis-inducing agent being adsorbed into the medical device. Thefibrosis-inducing agent may also be present on the surface of thedevice. The amount of surface associated fibrosis-inducing agent may bereduced by dipping the coated device into a solvent for thefibrosis-inducing agent or by spraying the coated device with a solventfor the fibrosis-inducing agent.

Fibrosis-Inducing Agent/Polymer with a Solvent

In one embodiment, the solvent is one that can be absorbed by the deviceand that can dissolve the device. The device can be immersed, eitherpartially or completely, in the fibrosis-inducing agent/solvent solutionfor a specific period of time (seconds to hours). The rate of immersioninto the fibrosis-inducing agent/solvent solution can be altered (e.g.,0.001 cm per sec to 50 cm per sec). The device can then be removed fromthe solution. The rate at which the device can be withdrawn from thesolution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). Thecoated device can be air-dried. The dipping process can be repeated oneor more times depending on the specific application. The device can bedried under vacuum to reduce residual solvent levels. In the preferredembodiment, the exposure time of the device to the solvent may be suchthat there is not significant permanent dimensional changes to thedevice (other than those associated with the coating itself). Thefibrosis-inducing agent may also be present on the surface of thedevice. The amount of surface associated fibrosis-inducing agent may bereduced by dipping the coated device into a solvent for thefibrosis-inducing agent or by spraying the coated device with a solventfor the fibrosis-inducing agent.

In the above description the device can be a device that has not beenmodified as well as a device that has been further modified by coatingwith a polymer (e.g., parylene), surface treated by plasma treatment,flame treatment, corona treatment, surface oxidation or reduction,surface etching, mechanical smoothing or roughening, or grafting priorto the coating process.

In another embodiment, a suspension of the fibrosis-inducing agent in apolymer solution can be prepared. The suspension can be prepared bychoosing a solvent that can dissolve the polymer but not thefibrosis-inducing agent or a solvent that can dissolve the polymer andin which the fibrosis-inducing agent is above its solubility limit. Insimilar processes described above, a device can be dipped into thesuspension of the fibrosis-inducing agent and polymer solution such thatthe device is coated with a polymer that has a fibrosing agent suspendedwithin it.

b) Spray Coating

Spray coating is another type of coating process that can be used. Inthe spray coating process, a solution or suspension of thefibrosis-inducing agent, with or without a polymeric or non-polymericcarrier, is nebulized and directed to the device to be coated by astream of gas. One can use spray devices such as an air-brush (forexample models 2020, 360, 175, 100, 200, 150, 350, 250, 400, 3000, 4000,5000, 6000 from Badger Air-brush Company, Franklin Park, Ill.), spraypainting equipment, TLC reagent sprayers (for example Part # 14545 and14654, Alltech Associates, Inc. Deerfield, Ill., and ultrasonic spraydevices (for example those available from Sono-Tek, Milton, N.Y.). Onecan also use powder sprayers and electrostatic sprayers.

In one embodiment, the fibrosis-inducing agent is dissolved in a solventfor the fibrosis agent and is then sprayed onto the device.

Fibrosis-Inducing Agent with an Inert Solvent

In one embodiment, the solvent is an inert solvent for the device suchthat the solvent does not dissolve the medical device to any greatextent and is not absorbed by the device to any great extent. The devicecan be held in place or the device can be mounted onto a mandrel or rodthat has the ability to move in an X, Y or Z plane or a combination ofthese planes. Using one of the above described spray devices, the devicecan be spray coated such that the device is either partially orcompletely coated with the fibrosis-inducing agent/solvent solution. Therate of spraying of the fibrosis-inducing agent/solvent solution can bealtered (e.g., 0.001 ml per sec to 10 ml per sec) to ensure that a goodcoating of the fibrosis-inducing agent is obtained. The coated devicecan be air-dried. The spray coating process can be repeated one or moretimes depending on the specific application. The device can be driedunder vacuum to reduce residual solvent levels. This process can resultin the fibrosis-inducing agent being coated on the surface of thedevice.

Fibrosis-Inducing Agent with a Swelling Solvent

In one embodiment, the solvent is one that can not dissolve the devicebut can be absorbed by the device. These solvents can thus swell thedevice to some extent. The device can be spray coated, either partiallyor completely, in the fibrosis-inducing agent/solvent solution. The rateof spraying of the fibrosis-inducing agent/solvent solution can bealtered (e.g., 0.001 ml per sec to 10 ml per sec) to ensure that a goodcoating of the fibrosis-inducing agent is obtained. The coated devicecan be air-dried. The spray coating process can be repeated one or moretimes depending on the specific application. The device can be driedunder vacuum to reduce residual solvent levels. This process can resultin the fibrosis-inducing agent being adsorbed into the medical device.The fibrosis-inducing agent may also be present on the surface of thedevice. The amount of surface associated fibrosis-inducing agent may bereduced by dipping the coated device into a solvent for thefibrosis-inducing agent or by spraying the coated device with a solventfor the fibrosis-inducing agent.

Fibrosis-Inducing Agent with a Solvent

In one embodiment, the solvent is one that can be absorbed by the deviceand that can dissolve the device. The device can be spray coated, eitherpartially or completely, in the fibrosis-inducing agent/solventsolution. The rate of spraying of the fibrosis-inducing agent/solventsolution can be altered (e.g., 0.001 ml per sec to 10 ml per sec) toensure that a good coating of the fibrosis-inducing agent is obtained.The coated device can be air-dried. The spray coating process can berepeated one or more times depending on the specific application. Thedevice can be dried under vacuum to reduce residual solvent levels. Thisprocess can result in the fibrosis-inducing agent being adsorbed intothe medical device as well as being surface associated. Preferably, theexposure time of the device to the solvent may be such as to not incursignificant permanent dimensional changes to the device. Thefibrosis-inducing agent may also be present on the surface of thedevice. The amount of surface associated fibrosis-inducing agent may bereduced by dipping the coated device into a solvent for thefibrosis-inducing agent or by spraying the coated device with a solventfor the fibrosis-inducing agent.

In one embodiment, the fibrosis-inducing agent and a polymer aredissolved in a solvent, for both the polymer and the fibrosing agent,and are then spray coated onto the device. In the above description, thedevice can be a device that has not been modified as well as a devicethat has been further modified by coating with a polymer (e.g.,parylene), surface treated by plasma treatment, flame treatment, coronatreatment, surface oxidation or reduction, surface etching, mechanicalsmoothing or roughening, or grafting prior to the coating process.

Fibrosis-Inducing Agent/Polymer with an Inert Solvent

In one embodiment, the solvent is an inert solvent for the device suchthat the solvent does not dissolve the medical device to any greatextent and is not absorbed by the device to any great extent. The devicecan be spray coated, either partially or completely, in thefibrosis-inducing agent/polymer/solvent solution for a specific periodof time. The rate of spraying of the fibrosis-inducing agent/solventsolution can be altered (e.g., 0.001 ml per sec to 10 ml per sec) toensure that a good coating of the fibrosis-inducing agent is obtained.The coated device can be air-dried. The spray coating process can berepeated one or more times depending on the specific application. Thedevice can be dried under vacuum to reduce residual solvent levels. Thisprocess can result in the fibrosis-inducing agent/polymer being coatedon the surface of the device.

Fibrosis-Inducing Agent/Polymer with a Swelling Solvent

In one embodiment, the solvent is one that can not dissolve the devicebut can be absorbed by the device. These solvents can thus swell thedevice to some extent. The device can be spray coated, either partiallyor completely, in the fibrosis-inducing agent/polymer/solvent solution.The rate of spraying of the fibrosis-inducing agent/solvent solution canbe altered (e.g., 0.001 ml per sec to 10 ml per sec) to ensure that agood coating of the fibrosis-inducing agent is obtained. The coateddevice can be air-dried. The spray coating process can be repeated oneor more times depending on the specific application. The device can bedried under vacuum to reduce residual solvent levels. This process canresult in the fibrosis-inducing agent/polymer being coated onto thesurface of the device as well as the potential for the fibrosis-inducingagent being adsorbed into the medical device. The fibrosis-inducingagent may also be present on the surface of the device. The amount ofsurface associated fibrosis-inducing agent may be reduced by dipping thecoated device into a solvent for the fibrosis-inducing agent or byspraying the coated device with a solvent for the fibrosis-inducingagent.

Fibrosis-Inducing Agent/Polymer with a Solvent

In one embodiment, the solvent is one that can be absorbed by the deviceand that can dissolve the device. The device can be spray coated, eitherpartially or completely, in the fibrosis-inducing agent/solventsolution. The rate of spraying of the fibrosis-inducing agent/solventsolution can be altered (e.g., 0.001 ml per sec to 10 ml per sec) toensure that a good coating of the fibrosis-inducing agent is obtained.The coated device can be air-dried. The spray coating process can berepeated one or more times depending on the specific application. Thedevice can be dried under vacuum to reduce residual solvent levels.Preferably, the exposure time of the device to the solvent may be suchas to not incur significant permanent dimensional changes to the device(other than those associated with the coating itself). Thefibrosis-inducing agent may also be present on the surface of thedevice. The amount of surface associated fibrosis-inducing agent may bereduced by dipping the coated device into a solvent for thefibrosis-inducing agent or by spraying the coated device with a solventfor the fibrosis-inducing agent.

In the above description, the device can be a device that has not beenmodified as well as a device that has been further modified by coatingwith a polymer (e.g., parylene), surface treated by plasma treatment,flame treatment, corona treatment, surface oxidation or reduction,surface etching, mechanical smoothing or roughening, or grafting priorto the coating process.

c) Direct Attachment

In certain embodiments, the fibrosis inducing agent can be attacheddirectly to the device. This can be accomplished by using an adhesive(e.g., cyanoacrylate, polymer/solvent solution), using a thermal processand or by sewing the fibrosis agent into or onto the device. In oneembodiment, the fibrosis inducing agent can be in the form of particles(irregular, regular, porous, spherical), threads, fibers, knits, weavesor electrospun material. For example, silk can be prepared as a knitted,woven or electrospun material. This material can then be placed on thesurface of the device. Sutures and/or an adhesive can then be used tosecure the silk material to the device.

In another embodiment, the fibrosis inducing agent can be dissolved in asuitable solvent. This solution can then be applied to the device usingan electrospraying or electrospinning process. Polymeric ornon-polymeric additives can be added to this solution to assist in theelectrospraying or electrospinning process and or to assist in theadhesion of the fibrosis inducing agent to the device. For example, silkcan be dissolved in HFIP and this can then be electrosprayed orelectrospun onto the device (e.g., stent).

In another embodiment, the fibrosis-inducing agent can be incorporatedinto the device during or post manufacture of the device. For examplesilk fibers could be woven into a hernia mesh to provide a product thatcontains the fibrosis-inducing agent that is incorporated into thedevice.

D. Methods for Utilizing Medical Implants

Medical devices and implants of the present invention may be utilized toinduce a fibrotic reaction around the device/implant that results in anenhanced bond between the tissue and the prosthesis. Such medicaldevices and implants provide a solution to the following common problemsassociated with a variety of clinical interventions.

1. Treatments for Degenerative Disc Disease (DDD)

Back pain is the number one cause of healthcare expenditures in theUnited States and accounts for over $50 billion in costs annually ($100billion worldwide). Over 12 million people in the U.S. have some form ofdegenerative disc disease (DDD) and 10% of them (1.2 million) canrequire surgery to correct their problem.

In healthy individuals, the vertebral column is composed of vertebralbone plates separated by intervertebral discs that form strong jointsand absorb spinal compression during movement. The intervertebral discis comprised of an inner gel-like substance called the nucleus pulposuswhich is surrounded by a tough fibrocartilagenous capsule called theannulus fibrosis. The nucleus pulposus is composed of a loose frameworkof collagen fibrils and connective tissue cells (resembling fibroblastsand chondrocytes) embedded in a gelatinous matrix of glycosaminoglycansand water. The annulus fibrosus is composed of numerous concentric ringsof fibrocartilage that anchor into the vertebral bodies. The most commoncause of DDD occurs when tears in the annulus fibrosis create an area oflocalized weakness that allow bulging, herniation or sequestration ofthe nucleus pulposis and annulus fibrosis into the spinal canal and/orspinal foramena. The bulging or herniated disc often compresses nervetissue such as spinal cord fibers or spinal cord nerve root fibers.Pressure on the spinal cord or nerve roots from the damagedintervertebral disc results in neuronal dysfunction (numbness, weakness,tingling), crippling pain, bowel or bladder disturbances and canfrequently cause long-term disability. Although many cases of DDD canspontaneously resolve, a significant number of patients can requiresurgical intervention in the form of minimally invasive procedures,microdiscectomy, major surgical resection of the disc, spinal fusion(fusion of adjacent vertebral bone plates using various techniques anddevices), and/or implantation of an artificial disc. The presentinvention provides for the application of an adhesion orfibrosis-inducing agent in the surgical management of DDD.

(i) Minimally Invasive Treatments of DDD

The present invention provides injectable compositions that iriclude abulking or filling agent and a fibrosing agent for direct injection intodamaged intervertebral discs. An injectable material containing afibrosis-inducing agent that can be injected into an intervertebral discspace (alone or in combination with polymeric carrier, which may be inthe form, e.g., of a gel, paste, or spray) is used to enhance scarringand support the annular ring of the disc (e.g., by inducing theproduction of fibrous tissue and fibrocartilage), thus reducing the riskof disc rupture and restoring disc function without surgery (embodimentsfor application during disc surgery are described below). In anotherembodiment, the injectable composition containing a fibrosis-inducingagent can further contain an agent that promotes bone growth ifpermanent fixation (immobilization) of adjacent vertebra is desired.

In this procedure, a needle is inserted into the intervertebral disc, aguidewire is advanced into the tissue and a dual lumen catheter (formany of the hydrogels described below such as COSEAL, COSTASIS, FLOSEAL,TISSEAL, VITOSS, and materials made from 4-armed thiol PEG (10K),4-armed NHS PEG(10K) and methylated collagen, such as described above ora single lumen catheter (for materials such as cyanoacrylate, CORTOSS,bone cement, apatitehydroxyapatite, calcium phosphate, calcium sulfate,hyaluronic acid, proteins, carbohydrates, sclerosing agents, and thelike) is advanced into the disc. When performing direct injection of theintervertebral disc, techniques can be used to enhance visualization ofneedle (or catheter) placement within the disc including, but notlimited to, the use of a needle coated with an ultrasound imagingcoating formulation, such as ECHO—COAT (Angiotech Pharmaceuticals, Inc.)or the addition of contrast agents (e.g., barium, tantalum, technitium,gadolinium, etc.) for localization by x-ray. After correct positioninghas been confirmed, the guidewire is removed, and a compositioncontaining a fibrosis-inducing agent, with or without a bone morphogenicprotein(s), and/or an osteogenic growth factor (such as transforminggrowth factor, platelet-derived growth factor, fibroblast growth factor)is injected via the catheter into the disc. Chemonucleolysis agents suchas collagenase, chymopapain or other tissue-degrading enzymes may alsobe used to chemically degrade the remaining disc tissue prior to theinjection of the fibrosing composition. Over time the fibrosis-inducingagent, with or without a bone morphogenic protein, and/or an osteogenicgrowth factor can encourage fibrous ankylosis, followed by bonyankylosis of the intervertebral space leading to increased stability andreduced pain.

The injectable material may contain a polymer system that can providesustained release of the fibrosis-inducing agent, bone morphogenicprotein, and/or osteogenic growth factor to enhance efficacy and reducethe need for repeat administrations of active agents. The polymericinjection material suitable for delivery of a fibrosis-inducing agent,bone morphogenic protein, and/or growth factor that promotes bone growthcan be either a non-degradable or a degradable material. Suitablenon-degradable materials include crosslinked compositions that comprisePVA, PVP, polyacrylamide, methyl methacrylate (MMA) and methylmethacrylate-styrene (MMA-styrene) which when mixed together formpolymethyl methacrylate (PMMA) or bone cement (e.g., SIMPLEX P made byStryker Howmedica, ZIMMER REGULAR and ZIMMER LOW VISCOSITY CEMENT,PALACOS, CMW-1 and CMW-2, ENDURANCE), synthetic cancellous bone voidfillers (e.g., CORTOSS), pHEMA, poly(vinyl PEG), poly(styrenesulfonate), poly(acrylic acid), poly(methacrylic acid), as well as otherpolymers that are known to form hydrogels. Other compositions includeblends and copolymers of the agents listed above. Suitable degradablematerials include, but are not limited to, resorbable ceramics composedof β-tricalcium phosphate (e.g., VITOSS and PROOSTEON 500R),hydroxyapatite or Ca₁₀(PO₄)₆OH (e.g., BIOOSS and OSTEOGRAF), calciumcarbonate or CaCO₃, calcium sulfate (e.g., OSTEOSET and ALLOMATRIX madeby Wright Medical Technology, Inc.), calcium phosphate (e.g., CALCIBONor NORIAN SRS), crosslinked materials of PEG, gelatin, collagen, boneallografts (e.g., ALLOGRO (Allosource Corporation, Centennial, Colo.),ORTHOBLAST (GenSci Regeneration Sciences, Inc., Canada), OPTEFORM(Exactech, Inc., Gainesville, Fla.), GRAFTON (Osteotech, Inc.,Eatontown, N.J.), mesenchymal stem cells, hyaluronic acid, hyaluronicacid derivatives, polysaccharides, carbohydrates, proteins (e.g.,albumin, casein, whey proteins, plant proteins, and fish proteins),autologous bone, demineralized bone matrix, cellulose derivatives (e.g.,HPC), chitosan, chitosan derivatives, polyester-polyalkylene oxide blockcopolymers (e.g., PLGA-PEG-PLGA and MePEG-PLGA, and the like) and otherlow molecular weight polymers that can be excreted. An injectablematerial of particular interest is prepared from a 4-armed thiol PEG(10K), a 4-armed NHS PEG(10K) and methylated collagen such as describedabove.

In a preferred embodiment, the injectable material also contains abiologically active agent capable of inducing fibrosis and ankylosis inthe disc space. In one embodiment, the injectable material is loadedwith a fibrosis-inducing agent and injected into the intervertebral discto help repair the annulus and prevent herniation of the nucleuspulposis. In another embodiment, the injectable material containsbiologically active agents capable of inducing bone growth such bonemorphogenic proteins and growth factors (transforming growth factor,platelet-derived growth factor, fibroblast growth factor) to promotebony ankylosis and fusion of adjacent vertebra.

In addition to, or in lieu of, fibrosis-inducing agents, bonemorphogenic proteins and growth factors, the injectable material can beutilized to deliver a sclerosant to the articular space. Sclerosantsinclude compounds such as ethanol, DMSO, surfactants, sucrose, NaCl,dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol,sodium tetradecyl sulfate, sodium morrhuate, sotradecol and others. Theinjectable material can further comprise agents such as glycerol,glycerin, PEG 200, triethyl citrate, and triacetin as plasticizers.

The injectable materials described above can be further modified to becomprised of, or contain, polymeric threads. Polymeric threads have theability to induce a fibroproliferative response from the surroundingtissue. These polymer threads can be degradable or non-degradable.Degradable threads can be composed of degradable polyesters,polyanhydrides, poly(anhydride esters), poly(ester-amides),poly(ester-ureas), polyorthoesters, polyphosphoesters, polyphosphazines,cyanoacrylate polymers, collagen, chitosan, hyaluronic acid, chromic catgut, alginates, starch, cellulose, cellulose esters, blends andcopolymers thereof, as well as other known degradable polymers.Non-degradable polymers that can be used include, but are not limitedto, polyesters (e.g., PET), polyurethanes, silicones, PE, PP, PS, PAA,PMA, silk, blends, copolymers thereof as well as other known polymers.The threads can be composed of a single composition or composed of ablend of differing compositions. The polymeric threads themselves can befurther modified through the addition of a polymeric coating applied tothe threads. The polymer used for coating the thread can be similar tothat described above for the threads themselves. The polymer coating mayfurther comprise a biologically active agent that has the ability toinduce a fibroproliferative or osteogenic response. The agents that canbe used are further described in the section (vi) below.

The injectable materials described above can be utilized to deliver aparticulate material that has the ability to induce fibrosis in theintervertebral disc. These particles can be either degradable ornon-degradable and are similar to those described above for threads.Additional particulate materials useful for the practice of thisembodiment include silk, talc, starch, glass, silicates, silica, calciumphosphate, calcium sulfate, calcium carbonate, hydroxyapatite, syntheticmineral (e.g., VITOSS and CORTOSS, PMMA, silver nitrate, ceramicparticles and other inorganic particles known in the art to induce afibroprqliferative response followed by mineralization. The particlesused in this embodiment can be all of the same composition or a blend ofdiffering compositions. These particles can also be used as a coatingapplied to the polymeric strands as described above.

The injectable materials can also be constructed such that it iscomprised of both polymeric threads and particles. The threads andparticles used are similar to those described above and may be ofuniform composition or blended composition. Virtually any combination ofthreads of differing compositions and particles of differingcompositions can be utilized in this embodiment. The hydrogel, thepolymeric threads, and the particles can all be utilized to deliver oneor more biologically active agents, as described below.

One specific composition comprises rods prepared from a methylatedcollagen-crosslinked poly(ethylene glycol) composition such as describedabove, which has powdered silk particles and/or mineral particles addedto the composition prior to curing. Once deployed, the rod can absorbwater, fill the disc space and adhere to any fibrocartilage or exposedbone. This expansion can prevent the rod from moving, while the powderedsilk and/or mineral particles can initiate an ankylosing response. Asthe material starts to degrade, the material can support the bone tissueingrowth that is initiated and potentiated by the particles. Bonemorphogenic proteins and/or growth factors (described previously andbelow) are also useful for inclusion in this composition. To furtherincrease the rate of initiation of this fibroproliferative response, asclerosant such as a surfactant (SDS), ethanolamine oleate or DMSO canbe added. In addition, one can also add or replace all (or a portion) ofthe 4-armed thiol PEG with a 4-armed amino PEG. The amino PEG canprovide a gel that can take a longer time to degrade and can providesome positive charge to further attract cellular material.

Another embodiment consists of an injectable implant composed of silkfibers or from a polymerized version of the fibrosing agent itself(i.e., repeating units of the fibrosing agent polymerized together).Bone morphogenic proteins and/or growth factors (described previouslyand below) also may be added to this composition.

In addition to the hydrogels, bone cements, and materials containingcalcium phosphate described above, there are several other injectablecompositions suitable for use in minimally invasive intervertebral discprocedures. All involve the deployment of a biomaterial into the nucleuspulposis with or without the addition of a fibrosis-inducing agent, bonemorphogenic protein(s), and/or a suitable growth factor(s). Thefollowing compositions can be delivered into the intervertebral disc viaspecialized delivery catheters, an endoscope, a needle or otherapplicator, a surgically placed drain or access port, or othertransdermal access device, including administration of: (a) fluids,suspensions, emulsions, microemulsions, microspheres, pastes, gels,microparticulates, sprays, aerosols, solid implants and otherformulations which release a biologically active fibrosis-inducingagent(s); (b) microparticulate silk and/or silk strands (linear,branched, and/or coiled) either alone, or loaded with an additionalfibrosis-inducing agent, bone morphogenic protein, and/or growth factorare also useful for directed injection into the intervertebral disc; (c)injectable collagen-containing formulations such as COSTASIS ormaterials made from 4-armed thiol PEG (10K), 4-armed NHS PEG(10K) andmethylated collagen such as described above, either alone, or loadedwith a fibrosis-inducing agent, bone morphogenic protein, and/or growthfactor, injected into the intervertebral disc; (d) injectablePEG-containing formulations such as COSEAL, FOCALSEAL, SPRAYGEL orDURASEAL, either alone, or loaded with a fibrosis-inducing agent, bonemorphogenic protein, and/or growth factor, injected into theintervertebral disc; (e) fibrinogen-containing formulations such asFLOSEAL or TISSEAL, either alone, or loaded with a fibrosis-inducingagent, bone morphogenic protein, and/or growth factor, injected into theintervertebral disc; (f) hyaluronic acid-containing formulations such asRESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT eitheralone, or loaded with a fibrosis-inducing agent, bone morphogenicprotein, and/or growth factor injected into the intervertebral disc; (g)polymeric gels for surgical implantation such as REPEL or FLOWGEL eitheralone, or loaded with a fibrosis-inducing agent, bone morphogenicprotein, and/or growth factor injected into the intervertebral disc; (h)orthopedic “cements” such as OSTEOBOND, low viscosity cement (LVC),SIMPLEX P, PALACOS, CORTOSS and ENDURANCE, either alone, or loaded witha fibrosis-inducing agent, bone morphogenic protein, and/or growthfactor injected into the intervertebral disc; (i) surgical adhesivescontaining cyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH,VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE andORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or as described above, eitheralone, or loaded with a fibrosis-inducing agent, bone morphogenicprotein, and/or growth factor, injected into the intervertebral disc;(j) surgical implants containing hydroxyapatite, calcium phosphate (suchas VITOSS), or calcium sulfate, alone or loaded with a fibrosis-inducingagent, bone morphogenic protein, and/or growth factor, injected into theintervertebral disc; (k) other biocompatible tissue fillers, such asthose made by BioCure, 3M Company and Neomend, either alone, or loadedwith a fibrosis-inducing agent, bone morphogenic protein, and/or growthfactor, injected into the intervertebral disc; (l) polysaccharide gelssuch as the ADCON series of gels, either alone, or loaded with afibrosis-inducing agent, bone morphogenic protein, and/or growth factor,injected into the intervertebral disc; (m) films, sponges or meshes suchas INTERCEED, VICRYL mesh, and GELFOAM either alone, or loaded with afibrosis-inducing agent, bone morphogenic protein, and/or growth factor,injected into the intervertebral disc; and/or (n) a hydrogel that isformed from an amino-functionalized polyethylene glycol (e.g., 4-armedtetra-amino PEG [10k]) and a 4-armed NHS functionalized PEG (e.g.,pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate[10K]). This hydrogel may further contain collagen, methylated collagenand/or gelatin. This hydrogel can further comprise the fibrosis-inducingagents described above (e.g., silk powder or silk threads). In many ofthese embodiments, it may also be useful to add a radio-opaque material(e.g., tantalum, barium, other metal, or a contrast material) such thatthe injected material can be visualized radiographically or by MRI.

It should be apparent to one of skill in the art that potentially anyfibrosis-inducing agents described above may be utilized alone, or incombination, in the practice of this embodiment. Exemplary fibrosingagents for use in spinal prostheses (e.g., devices and bulking agents)include talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin,and CTGF, as well as analogues and derivatives of the aforementioned.

Optionally, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, or growth hormone) and/or a bone morphogenic protein(BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogueor derivative thereof).

Furthermore, the device may comprise an agent that stimulates cellularproliferation. Examples include: dexamethasone, isotretinoin (13-cisretinoic acid), 17-β-estradiol, estradiol, 1-a-25 dihydroxyvitamin D₃,diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid(ATRA), and analogues and derivatives thereof. The administration anddosages of these agents for use in these embodiments are described insection (vi) below.

(ii) Open Surgical Disc Resection and Microdiscectomy

Spinal disc removal is mandatory and urgent in cauda equine syndromewhen there is a significant neurological deficit; particularly bowel orbladder dysfunction. It is also performed electively to relieve pain andeliminate lesser neurological symptoms.

For open surgical resection of a ruptured lumbar disc (laminectomy) thepatient is placed in a modified kneeling position under generalanesthesia. An incision is made in the posterior midline and the tissueis dissected away to expose the appropriate interspace; the ligamentumflavum is dissected and in some cases portions of the bony lamina areremoved to allow adequate visualization. The nerve root is carefullyretracted away to expose the herniated fragment and the defect in theannulus. Typically, the cavity of the disc is entered from the tear inthe annulus and the loose fragments of the nucleus pulposus are removedwith pituitary forceps. Any additional fragments of disc sequesteredinside or outside of the disc space are also carefully removed and thedisc space is forcefully irrigated to remove to remove any residualfragments. If tears are present in the dura, the dura is closed withsutures that are often augmented with fibrin glue. The tissue is thenclosed with absorbable sutures.

Microlumbar disc excision (microdiscectomy) can be performed as anoutpatient procedure and has largely replaced laminectomy as theintervention of choice for herniated discs. A one inch incision is madefrom the spinous process above the disc affected to the spinous processbelow. Using an operating microscope, the tissue is dissected down tothe ligamentum flavum and bone is removed from the lamina until thenerve root can be clearly identified. The nerve root is carefullyretracted and the tears in the annulus are visualized undermagnification. Microdisc forceps are used to remove disc fragmentsthrough the annular tear and any sequestered disc fragments are alsoremoved. As with laminectomy, the disc space is irrigated to remove anydisc fragments, any dural tears are repaired and the tissue is closedwith absorbable sutures. It should be noted that anterior (abdominal)approaches can also be used for both open and endoscopic lumbar discexcision. Cervical and thoracic disc excisions are similar to lumbarprocedures and can also be performed from a posterior approach (withlaminectomy) or as an anterior discectomy with fusion.

The present invention provides injectable compositions to promotescarring of the annulus, scarring of dural defects and stabilization ofadjacent vertebra. The fibrosing agent or fibrosing agent containingcomposition is delivered under direct vision during open or endoscopicdisc excision. Here the composition containing the fibrosis-inducingagent is applied to the annulus or the dural defect directly (in opensurgical procedures) or through the side port of an endoscope. Thefibrosis-inducing agent can assist in the production of strong fibrotictissue in the annulus fibrosis at the previous site of herniation orrupture. This can reinforce the weak portion of the intervertebral discand reduce the likelihood of subsequent re-rupture. In dural defects,the fibrosis-inducing agent can assist in the healing of the dura andprevent complications such as CSF leakage.

The material may also be composed of a polymer system to providesustained release of the fibrosis-inducing agent. The material suitablefor delivery of a fibrosis-inducing agent for the purposes of thisinvention can be composed of a non-degradable or a degradable material.Suitable non-degradable materials can include crosslinked compositionsthat comprise PVA, PVP, polyacrylamide, methyl methacrylate (MMA) andmethyl methacrylate styrene (MMA-styrene) which when mixed together formpolymethyl methacrylate (PMMA) or bone cement (e.g., SIMPLEX P ZIMMERREGULAR or ZIMMER LOW VISCOSITY CEMENT, PALACOS, CMW-1, CMW-2 orENDURANCE), synthetic cancellous bone void fillers (e.g., CORTOSS),PHEMA, poly(vinyl PEG), poly(styrene sulfonate), poly(acrylic acid),poly(methacrylic acid), as well as other polymers that are known to formhydrogels. Additional compositions include blends and copolymers of theagents listed above. Suitable degradable materials include, but are notlimited to, resorbable ceramics composed of β-tricalcium phosphate(e.g., VITOSS and PROOSTEON 500R), hydroxyapatite or Ca₁₀(PO₄)₆OH (e.g.,BIOOSS, OSTEOGRAF), calcium carbonate or CaCO₃, calcium sulfate (e.g.,OSTEOSET and ALLOMATRIX), calcium phosphate (e.g., CALCIBON or NORIANSRS), crosslinked materials of PEG, gelatin, collagen, bone allografts(e.g., ALLOGRO, ORTHOBLAST, OPTEFORM, GRAFTON), mesenchymal stem cells,hyaluronic acid, hyaluronic acid derivatives, polysaccharides,carbohydrates, proteins (e.g., albumin, casein, whey proteins, plantproteins, and fish proteins), autologous bone, demineralized bonematrix, cellulose derivatives (HPC etc), chitosan, chitosan derivatives,polyester-polyalkylene oxide block copolymers (e.g., PLGA-PEG-PLGA andMePEG-PLGA, and the like) and other low molecular weight polymers thatcan be excreted.

One material that is of particular interest for use in annulus and duralrepairs during intervertebral disc surgery is an injectable materialprepared from a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) andmethylated collagen such as described above. In a preferred embodiment,the injectable material also contains a biologically active agentcapable of inducing fibrosis to reinforce the annulus fibrosis (toreduce the risk of repeat herniation or rupture) or assist in the repairof dural defects (to prevent CSF leaks). Preferred biologically activeagents for use in combination with the injectable material includefibrosis-inducing agents and growth factors (e.g., transforming growthfactor, platelet-derived growth factor, fibroblast growth factor), whosedosages and release kinetics are all described in detail in section (vi)below.

The materials described above can further modified to be comprised of,or contain, polymeric threads. Polymeric threads have the ability toinduce a fibroproliferative response in the annulus fibrosis or thedura. These polymer threads can be degradable or non-degradable.Degradable threads can be composed of degradable polyesters,polyanhydrides, poly(anhydride esters), poly(ester-amides),poly(ester-ureas), polyorthoesters, polyphosphoesters, polyphosphazines,cyanoacrylate polymers, collagen, chitosan, hyaluronic acid, chromic catgut, alginates, starch, cellulose, cellulose esters, blends andcopolymers thereof, as well as other known degradable polymers.Non-degradable polymers that can be used include, but are not limitedto, polyesters (e.g., PET), polyurethanes, silicones, PE, PP, PS, PM,PMA, silk, blends, copolymers thereof. The threads used can be composedof a single composition or composed of a blend of differingcompositions. The polymeric threads themselves can be further modifiedthrough the addition of a polymeric coating applied to the threads. Thepolymer used for coating the thread can be similar to that describedabove for the threads themselves. The polymer coating may furthercomprise a biologically active agent that has the ability to induce afibroproliferative response. The agents that can be used are furtherdescribed in the section (vi) below.

The materials described above can also be utilized to deliver aparticulate material that has the ability to induce fibrosis. Theseparticles can be either degradable or non-degradable and are similar tothose described above for threads. In addition to those, particulatematerials useful for the practice of this embodiment include silk, talc,starch, glass, silicates, silica, calcium phosphate, calcium sulfate,calcium carbonate, hydroxyapatite, synthetic mineral (e.g., VITOSS andCORTOSS), PMMA, silver nitrate, ceramic particles and other inorganicparticles known in the art to induce a fibroproliferative responsefollowed by mineralization. The particles used in this embodiment can beall of the same composition or a blend of differing compositions. Theseparticles can also be used as a coating applied to the polymeric strandsas described above.

As is readily apparent, the materials used in the present invention canalso be constructed such that they are comprised of both polymericthreads and particles. The threads and particles used are similar tothose described above and may be of uniform composition or blendedcomposition. Virtually any combination of threads of differingcompositions and particles of differing compositions can be utilized inthis embodiment. The hydrogels (e.g., injectable materials prepared froma 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and methylatedcollagen), the polymeric threads, and the particles can all be utilizedto deliver one or more biologically active agents, as described below.

Other compositions are suitable for use in open surgical disc resectionand microdiscectomy. All involve the deployment of a biomaterial and afibrosis-inducing agent to reinforce the annulus fibrosis or assist indural repair. The following compositions can be delivered duringsurgical disc resection and microdiscectomy either directly, usingspecialized delivery catheters, via an endoscope, or through a needle orother applicator: (a) fluids, suspensions, emulsions, microemulsions,microspheres, pastes, gels, microparticulates, sprays, aerosols, solidimplants and other formulations which release a fibrosis-inducingagent(s); (b) microparticulate silk and/or silk strands (linear,branched, and/or coiled) either alone, or loaded with an additionalfibrosis-inducing agent and/or growth factor; (c) collagen-containingformulations such as COSTASIS or materials made from 4-armed thiol PEG(10K), 4-armed NHS PEG (10K) and methylated collagen such as describedabove, either alone, or loaded with a fibrosis-inducing agent and/orgrowth factor; (d) injectable PEG-containing formulations such asCOSEAL, FOCALSEAL, SPRAYGEL or DURASEAL loaded with a fibrosis-inducingagent and/or growth factor; (e) fibrinogen-containing formulations suchas FLOSEAL or TISSEAL loaded with a fibrosis-inducing agent and/orgrowth factor; (f) hyaluronic acid-containing formulations such asRESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT loaded witha fibrosis-inducing agent and/or growth factor; (g) polymeric gels forsurgical implantation such as REPEL or FLOWGEL loaded with afibrosis-inducing agent and/or growth factor injected into the jointspace; (h) orthopedic “cements” such as OSTEOBOND, LVC, SIMPLEX P,PALACOS, CORTOSS, and ENDURANCE loaded with a fibrosis-inducing agentand/or growth factor; (i) surgical adhesives containing cyanoacrylatessuch as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND,TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUIDPROTECTANT or as described above, loaded with a fibrosis-inducing agentand/or growth factor; (j) surgical implants containing hydroxyapatite,calcium phosphate (such as VITOSS, Orthovita), or calcium sulfate loadedwith a fibrosis-inducing agent and/or growth factor; (k) otherbiocompatible tissue fillers, such as those made by BioCure, 3M Companyand Neomend loaded with a fibrosis-inducing agent and/or growth factor;(l) polysaccharide gels such as the ADCON series of gels loaded with afibrosis-inducing agent and/or growth factor; (m) films, sponges ormeshes such as INTERCEED, VICRYL mesh, and GELFOAM either alone, orloaded with a fibrosis-inducing agent, bone morphogenic protein, and/orgrowth factor, injected into the intervertebral disc; and/or (n) ahydrogel that is formed from an amino-functionalized polyethylene glycol(e.g., 4-armed tetra-amino PEG [10k]) and a 4-armed NHS functionalizedPEG (e.g., pentaerythritol poly(ethylene glycol)ethertetra-succinimidylglutarate [10K]). This hydrogel mayfurther contain collagen, methylatedcollagen and/or gelatin. This hydrogel can further comprise thefibrosis-inducing agents described above (e.g., silk powder or silkthreads). and/or (m) films, sponges or meshes such as INTERCEED, VICRYLmesh, and GELFOAM either alone, or loaded with a fibrosis-inducing agentand/or growth factor.

It should be apparent to one of skill in the art that potentially anyfibrosis-inducing agents described above may be utilized alone, or incombination, in the practice of this embodiment. Exemplary fibrosingagents for use in spinal prostheses (e.g., devices and bulking agents)include talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin,and CTGF, as well as analogues and derivatives of the aforementioned.

Optionally, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, and growth hormone) and/or a bone morphogenicprotein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or ananalogue or derivative thereof).

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.The administration and dosages of these agents for use in theseembodiments are described in section (vi) below.

(iii) Treatments of Vertebral Compression Fractures

Osteoporosis is a progressive degenerative bone disease characterized bydecreased bone mineral density, degradation of bone microarchitectureand reduced bone strength. The weakened bone is often unable towithstand stress, or even normal weight-bearing activities, and is at anincreased risk for sustaining fractures. Fractures are the most commonclinical manifestation of osteoporosis and the condition is oftenasymptomatic until the breakage occurs. Osteoporosis is the cause of 1.3million fractures each year in the U.S. and is estimated to cost thehealthcare system over $10 billion annually. Fractures of the hip, wristand other long bones are common in osteoporosis, but approximately550,000 patients in the U.S. (700,000 worldwide) suffer vertebralcompression fractures as a result of their disease. Here, the weakenedcancellous bone of the vertebral column essentially collapses(compresses) under the weight placed on it during normal activities andthe vertebra loses height (i.e., the center of the vertebra collapsesand the two endplates of the vertebra move closer together). Compressionof the vertebra leads to pain, a loss of height, curvature of the spine(kyphosis), and in some cases, breathing problems due to pressure placedon the chest cavity and lungs.

Traditionally, vertebral compression fractures have been treatedconservatively with bed rest. In severe cases, spinal fusion and/or openfracture reduction (repairing the fracture with surgically placedorthopedic plates and screws) have also been used in the management ofvertebral compression fractures. Recently, two minimally invasiveprocedures—vertebroplasty and kyphoplasty—have been developed to treatvertebral compression fractures due to osteoporosis or, less commonly,due to bone tumors. Vertebroplasty utilizes bone cement(polymethylmethacrylate —PMMA) injected under pressure into the fractureunder x-ray guidance to stabilize the fracture, provide support andreduce pain. This procedure can often be performed as an outpatient andprovides almost immediate symptomatic relief and early mobilization.Kyphoplasty involves the insertion of a balloon (KYPHX Inflatable BoneTamp made by Kyphon Inc., Sunnyvale, Calif.) into the fracture which isthen inflated inside the bone to create a void, stabilize the fractureand straighten the bone and spine (i.e., restore the vertebral heightlost as a result of the compression fracture). The surgeon then injectsbone filler (typically PMMA or a calcium phosphate-based material) viaspecialized access devices (Inflation Syringe and Bone Access Systemalso made by Kyphon, Inc. (Sunnyvale, Calif.) into the space under C-armimage-guided fluoroscopy to support the fractured vertebra). Injectingthe bone cement into the balloon-created cavity enables the injection tobe performed under low pressure and reduces the incidence ofneurological injury associated with cement leakage. In vertebroplasty,where the cement is injected under pressure, cement leakage occurs in30-73% of patients versus only 8-9% of those treated with kyphoplasty.

In both vertebroplasty and kyphoplasty the fractured bone is reinforcedand replaced by bone cement. Unfortunately, bone cement is significantlystronger than the adjacent bone and can exert an incompressible masseffect on the surrounding vertebra leading to compressions and fracturesin the vertebra above and below the treated segment. The presentinvention provides injectable compositions that include a bulking orfilling agent and a fibrosing agent for direct injection into vertebralcompression fractures as part of vertebroplasty or kyphoplasty. Amaterial containing a fibrosis-inducing agent (alone or in combinationwith polymeric carrier, which may be in the form of, e.g., a gel, paste,or spray) is injected into a vertebral compression fracture can be usedto promote the growth of endogenous scar tissue to fill the vertebralbody defect, thus more closely mimicking normal tissue dynamics andreducing the incidence of adjacent vertebral fractures. In anotherembodiment, the injectable composition containing a fibrosis-inducingagent can further contain an agent that promotes bone growth (e.g., bonemorphogenic proteins, growth factors, etc.). When performing aninjection into a vertebral compression fracture, it may also benecessary to add compositions to enhance visualization of needle (orcatheter). Suitable agents and methods for use in combination with afibrosis-inducing agent (with or without an agent that promotes bonegrowth) include, but are not limited to, the use of a needle coated withECHO—COAT or the addition of contrast agents (e.g., barium, tantalum,technitium, gadolinium) for localization by x-ray or MRI.

The injectable material may also contain a polymer system that canprovide sustained release of the fibrosis-inducing agent (with orwithout a concominant bone morphogenic protein, and/or osteogenic growthfactor) to enhance efficacy and reduce the need for repeatadministrations of active agents. Preferred polymeric carriers fordelivery of a injectable fibrosis-inducing agent (with or without a bonemorphogenic protein, and/or growth factor that promotes bone growth) forthe treatment of vertebral compression fractures are degradablematerials which, after providing initial tissue support, are graduallyreplaced by the body's own scar tissue. Suitable degradable materialsfor use in this embodiment include, but are not limited to, resorbableceramics composed of β-tricalcium phosphate (e.g., VITOSS and PROOSTEON500R), hydroxyapatite or Ca₁₀(PO₄)₆OH (e.g., BIOOSS and OSTEOGRAF),calcium carbonate or CaCO₃, calcium sulfate (e.g., OSTEOSET andALLOMATRIX), calcium phosphate (e.g., CALCIBON or NORIAN SRS),crosslinked materials of PEG, gelatin, collagen, bone allografts (e.g.,ALLOGRO, ORTHOBLAST, OPTEFORM, GRAFTON), mesenchymal stem cells,hyaluronic acid (such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC,SEPRAFILM, SEPRACOAT), hyaluronic acid derivatives, polysaccharides,carbohydrates, fibrinogen-containing formulations (such as FLOSEAL orTISSEAL), proteins (e.g., albumin, casein, whey proteins, plantproteins, and fish proteins, and the like), autologous bone,demineralized bone matrix, cellulose derivatives (e.g., HPC etc),chitosan, chitosan derivatives, polyester-polyalkylene oxide blockcopolymers (e.g., PLGA-PEG-PLGA and MePEG-PLGA, and the like) and otherlow molecular weight polymers that can be excreted. InjectablePEG-containing formulations such as COSEAL, FOCALSEAL, SPRAYGEL orDURASEAL loaded with a fibrosis-inducing agent, bone morphogenicprotein, and/or growth factor can also be used for injection into avertebral compression fracture. Loading these materials with afibrosis-inducing agent (with or without a bone morphogenic protein,and/or growth factor that promotes bone growth) can produce aninjectable material that can provide initial support and symptomaticrelief, but degrade with time as the body's own scar tissue grows in torepair the defect.

One injectable material that is of particular interest for injectioninto vertebral compression fractures is prepared from a 4-armed thiolPEG (10K), a 4-armed NHS PEG(10K) and methylated collagen such asdescribed above. In a preferred embodiment, the injectable material alsocontains a biologically active fibrosis-inducing agent (with or withouta bone morphogenic protein, and/or growth factor that promotes bonegrowth). In one embodiment, the injectable material is loaded with afibrosis-inducing agent is injected into a vertebral compressionfracture to provide stability and symptomatic relief, form a scaffoldthat supports fibrous and bony ingrowth, deliver active agents that canpromote repair, and degrade once tissue repair is complete. In anotherembodiment, the injectable material contains biologically active agentscapable of inducing bone growth such bone morphogenic proteins andgrowth factors (transforming growth factor, platelet-derived growthfactor, fibroblast growth factor) to promote bony ankylosis and fusionof adjacent vertebra. In some circumstances, the injectable material maycontain a fibrosis-inducing agent as well as a bone morphogenic proteinand/or growth factors that promote bone growth.

In certain embodiments (for example, in the treatment of more unstablefractures) it may be desirable to use a bone cement to deliver thefibrosis-inducing agent to a vertebral compression fracture. Suitablenon-degradable materials include crosslinked compositions that comprisePVA, PVP, polyacrylamide, methyl methacrylate (MMA) and methylmethacrylate styrene (MMA-styrene) which when mixed together formpolymethyl methacrylate (PMMA) or bone cement (e.g., SIMPLEX P, ZIMMERREGULAR and ZIMMER LOW VISCOSITY CEMENT, PALACOS, CMW-1, CMW-2 orENDURANCE). Also of utility in this embodiment are synthetic cancellousbone void fillers (e.g., CORTOSS), PHEMA, poly(vinyl PEG), poly(styrenesulfonate), poly(acrylic acid), poly(methacrylic acid), as well as otherpolymers that are known to form hydrogels. Surgical adhesives containingcyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH, TISSUEMEND,VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANTloaded with a fibrosis-inducing agent, bone morphogenic protein, and/orgrowth factor are also suitable for injection into vertebral compressionfracture. Additional compositions include blends and copolymers of theagents listed above. In each case the material is loaded with afibrosis-inducing agent (with or without a bone morphogenic protein,and/or growth factor that promotes bone growth) and injected into avertebral compression fracture (as part of vertebroplasty orkyphoplasty) to stabilize the fracture and encourage the ingrowth oftissue. The addition of fibrous tissue in and around the non-degradableimplant can make the material behave more like native tissue and reducethe incidence of adjacent fractures.

All of the injectable materials described above can be further modifiedto be comprised of, or contain, polymeric threads. Polymeric threadshave the ability to induce a fibroproliferative response from thesurrounding tissue. These polymer threads can be degradable ornon-degradable. Degradable threads can be composed of degradablepolyesters, polyanhydrides, polyorthoesters, polyphosphoesters,polyphosphazines, cyanoacrylate polymers, collagen, chitosan, hyaluronicacid, chromic cat gut, alginates, starch, cellulose, cellulose esters,blends and copolymers thereof, as well as other known degradablepolymers. Non-degradable polymers that can be used include, but are notlimited to, polyesters (e.g., PET), polyurethanes, silicones, PE, PP,PS, PM, PMA, silk, blends, copolymers thereof as well as other knownpolymers. The threads used can be composed of a single composition orcomposed of a blend of differing compositions. The polymeric threadsthemselves can be further modified through the addition of a polymericcoating applied to the threads. The polymer used for coating the threadcan be similar to that described above for the threads themselves. Thepolymer coating may further comprise a biologically active agent thathas the ability to induce a fibroproliferative or osteogenic response.The fibrosis-inducing agents that can be used are further described inthe section (vi) below.

The injectable materials described above can be utilized to deliver aparticulate material that has the ability to induce fibrosis in anintervertebral fracture. These particles can be either degradable ornon-degradable and are similar to those described above for threads.Microparticulate silk and/or silk strands (linear, branched, and/orcoiled) either alone, or loaded with an additional fibrosis-inducingagent, bone morphogenic protein, and/or growth factor are also usefulfor directed injection into a vertebral compression fracture. Additionalparticulate materials useful for the practice of this embodiment includetalc, starch, glass, silicates, silica, calcium phosphate, calciumsulfate, calcium carbonate, hydroxyapatite, synthetic mineral (e.g.,VITOSS and CORTOSS), PMMA, silver nitrate, ceramic particles and otherinorganic particles known in the art to induce a fibroproliferativeresponse followed by mineralization. The particles used in thisembodiment can be all of the same composition or a blend of differingcompositions. These particles can also be used as a coating applied tothe polymeric strands as described above.

The injectable materials can also be constructed such that it iscomprised of both polymeric threads and particles. The threads andparticles used are similar to those described above and may be ofuniform composition or blended composition. Virtually any combination ofthreads of differing compositions and particles of differingcompositions can be utilized in this embodiment. The hydrogels, thepolymeric threads, and the particles can all be utilized to deliver oneor more biologically active agents, as described below.

One specific composition comprising threads and/or particles is preparedfrom 4-armed thiol PEG (10K), 4-armed NHS PEG(10K) and methylatedcollagen such as described above and contains powdered silk particles(or silk threads) and/or mineral particles added to the compositionprior to curing. Once deployed, the composition can absorb water, fillthe fracture space and adhere to adjacent bone. This expansion canstabilize the fracture and restore vertebral height, while the powderedsilk and/or mineral particles can initiate an ankylosing response. Asthe 4-armed thiol PEG (10K), 4-armed NHS PEG(10K) and methylatedcollagen composition starts to degrade, the material can support thebone tissue ingrowth that is initiated and potentiated by the particles.Bone morphogenic proteins and/or growth factors (described previouslyand below) are also useful for inclusion in this composition. Inaddition, one may also add or replace all (or a portion) of the 4-armedthiol PEG with a 4-armed amino PEG. The amino PEG can provide a gel thatcan take a longer time to degrade and can provide some positive chargeto further attract cellular material.

A second specific embodiment consists of an injectable implant composedof silk fibers or a polymerized version of the fibrosing agent itself(i.e., repeating units of the fibrosing agent polymerized together).Bone morphogenic proteins and/or growth factors (described previouslyand below) may also be added to this composition.

It should be apparent to one of skill in the art that potentially anyfibrosis-inducing agents described above may be utilized alone, or incombination, in the practice of this embodiment. Exemplary fibrosingagents for use in spinal prostheses (e.g., devices and bulking agents)include talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin,and CTGF, as well as analogues and derivatives of the aforementioned.

Optionally, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, and growth hormone) and/or a bone morphogenicprotein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or ananalogue or derivative thereof).

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

The administration and dosages of these agents for use in the aboveembodiments are described in section (vi) below.

(iv) Spinal Fusion Devices

In some cases, it may be necessary to promote bony fusion of adjacentvertebral segments (in effect biologically “welding” the segmentstogether). Fusion of one or more vertebral segments alleviates pain byrestricting vertebral motion across the damaged intervertebral disc(s).Surgical spinal fusion can be accomplished using a variety ofprocedures, implants and devices.

Typically, the vertebral canal is exposed through open surgery (eitheranteriorly and/or posteriorly) and all or parts of the damaged disc areremoved sufficient to allow decompression of the affected cord or nerveroots. Bone grafts (autografts or allografts) or bone substitutes areused to promote vertebral fusion, while the fixation devices serve toimmobilize the region until bony fixation takes place. As part of thespinal fusion surgery, it is often necessary to augment the procedurethrough the insertion of an implant or device that stabilizes the fusingspinal segments while the bone graft or bone substitute fuses the mobilesegments. Examples of implants and devices designed to splint thesegments during the healing process include: fusion devices (includingfusion baskets, fusion cage apparatus, interbody cages, interbodyimplants, fusion cage anchoring devices, fusion stabilization chamber,fusion cage anchoring plates), bone fixation devices (includinganchoring bone plates, bone screws, and other fixation hardware) andtissue fillers/implants (including bone cement, allograft material,autograft material, collagen, and other biocompatible tissue fillers).All of these implants are suitable for coating with, or delivery of, afibrosis-inducing agent(s) to promote healing and accelerate fusion ofthe vertebral bodies.

Spinal fusion cages are interbody devices that fit within theintervertebral space and/or the anterior region of the vertebral column.Fusion cages have various shapes including rectangular or cylindricaland a plurality of openings and helical threading. Fusion cages areoften composed of an outer body and a hollow cavity that may or may notbe used to insert bone growth-promoting material for stimulating bonefusion. For example, the prosthesis may be an interbody fusion cage thathas an externally threaded stem projecting from a domed outer end whichis fixed using an assembly of a plate, a fastener and bone screws. Seee.g., U.S. Pat. No. 6,156,037. The prosthesis may be a fusion cage witha threaded outer surface adapted for promoting fusion with bonestructures when a bone-growth-inducing substance is packed into the cagebody. See e.g., U.S. Pat. Nos. 4,961,740; 5,015,247; 4,878,915; and4,501,269. The prosthesis may be a generally tubular shell with ahelical thread projecting with a plurality of pillars with holes tofacilitate bone ingrowth and mechanical anchoring (see e.g., U.S. Pat.Nos. 6,071,310 and 5,489,308) or it may be biologically active and serveto promote fusion with the adjacent vertebral bone plates (see e.g.,U.S. Pat. Nos. 5,489,308 and 6,520,993). Other U.S. patents thatdescribe threaded spinal implants include U.S. Pat. Nos. 5,263,953;5,458,638; and 5,026,373.

In another aspect, the prosthesis may be a bone fixation device designedto promote vertebral fusion in order to limit movement between adjacentvertebrae. For example, bone dowels, rods, hooks, wires, wedges, plates,screws and other components may be used to fix the vertebral segmentsinto place. The fixation device may fit within the intervertebral spaceor it may encompass both the intervertebral space and the anteriorregion of the vertebral column or it may only encompass the anteriorregion of the vertebral column. A bone fixation device may be used witha fusion cage to assist in stabilizing the device within theintervertebral area. For example, the prosthesis may be in the form of asolid annular body having a plurality of discrete bone-engaging teethprotruding on the superior and inferior surfaces and having a centralopening that may be filled with a bone growth-promoting material. Seee.g., U.S. Pat. No. 6,520,993. The prosthesis may have a disk-like bodywith weld-like raised parts disposed on opposite surfaces to enhancelateral stability in situ. See e.g., U.S. Pat. No. 4,917,704. Theprosthesis may be composed of opposite end pieces that maintain theheight of the intervertebral space with an integral central element thatis smaller in diameter wherein osteogenic material is disposed withinthe annular pocket between the end pieces. See e.g., U.S. Pat. No.6,146,420. The prosthesis may be composed of first and second sidesurfaces extending parallel to each other with upper and lower surfacesthat engage the adjacent vertebrae. See e.g., U.S. Pat. No. 5,716,415.The prosthesis may be a fusion stabilization chamber composed of ahollow intervertebral spacer and an end portion with at least one holefor affixing into the surrounding bone. See e.g., U.S. Pat. No.6,066,175. The prosthesis may be composed of a metallic body taperingconically from the ventral to the dorsal end and having a plurality offishplates extending from opposite sides with openings for bone screws.See e.g., U.S. Pat. No. 4,955,908. The prosthesis may be composed of apair of plates which may have protrusions for engaging the adjacentvertebrae and an alignment device disposed between the engaging platesfor separating the plates to maintain them in lordotic alignment. Seee.g., U.S. Pat. No. 6,576,016. The prosthesis may be a plurality ofimplants that are inserted side by side into the disc space to promotebone fusion across an intervertebral space. See e.g., U.S. Pat. No.5,522,899. The prosthesis may be an anchoring device composed of ananchoring plate with a central portion configured for attachment to avertebral implant (e.g., fusion cage) and the end portions adapted tofasten in a fixed manner to a bony segment of the vertebra. See e.g.,U.S. Pat. No. 6,306,170. The prosthesis may be a bone fixation apparatuscomposed of a bone plate and a fastener apparatus (e.g., bone screws).See e.g., U.S. Pat. Nos. 6,342,055; 6,454,769; 6,602,257; and 6,620,163.

Spinal prostheses, which may be combined with one or morefibrosis-inducing agents according to the present invention, includecommercially available products. Examples include: the INTERFIX ThreadedFusion Device (by Medtronic Sofamor Danek, Memphis, Term.), the BAK/CCervical Interbody Fusion System and the CERVI-LOK Cervical FixationSystem (by Centerpulse SPINE-TECH, Minneapolis, Minn.), the SC-ACUFIXAnterior Cervical Plate System (by Spinal Concepts, Austin, Tex.), theACROFLE TDR prostheses and the CHARITE Artificial Disc (by DePuy Spine,Inc., Raynham, Mass.), the PRODISC system and PRODISC Cervical-C IDEdisc replacement (by Synthes-Stratec, Switzerland) and the PROSTHETICDISC NUCLEUS (by Raymedica, Inc., Minneapolis, Minn.).

In all of the aforementioned spinal fusion devices, the addition of afibrosis-inducing agent may assist in the spinal fusion process bypromoting the production of fibrous tissue. In one aspect, the presentinvention provides spinal fusion devices (including fusion baskets,fusion cage apparatus, interbody cages, interbody implants, fusion cageanchoring devices, fusion stabilization chamber, fusion cage anchoringplates; bone fixation devices including anchoring bone plates, bonescrews, and other fixation hardware; and tissue fillers/implantsincluding bone cement, allograft material, autograft material, collagen,and other biocompatible tissue fillers) that include a fibrosis-inducingagent or a composition that includes a fibrosis-inducing agent topromote scarring and fixation of the device into the surrounding bone.In one aspect, a spinal fusion device is coated with a fibrosing agentor a composition that includes the fibrosing agent to enhance healing.In another aspect, the fibrosing agent may be incorporated into theglue/cement that holds the spinal fusion device in place. In anotheraspect, the spinal fusion device is covered (all or in part) with a silkmesh or lattice to encourage scarring and anchoring into the surroundingbone. For example, a silk mesh or lattice can be coated onto all or aportion of the surface of fusion cage or other bone fixation hardware toencourage scarring and anchoring into the surrounding bone.

Numerous polymeric and non-polymeric carrier systems describedpreviously can be used to provide sustained release of thefibrosis-inducing agent from the spinal fusion device. Methods forincorporating fibrosing compositions onto or into the spinal fusiondevices include: (a) directly affixing to the device a fibrosingcomposition (e.g., by either a spraying process or dipping process asdescribed above, with or without a carrier); (b) directly incorporatinginto the device a fibrosing composition (e.g., by either a sprayingprocess or dipping process as described above, with or without acarrier); (c) by coating the device with a substance such as a hydrogelwhich can in turn absorb the fibrosing composition; (d) by interweavinga fibrosing composition (for example a silk strand or another polymericthread which releases a fibrosis-inducing agent) into the devicestructure; (e) by inserting the device into a sleeve or mesh which iscomprised of, or coated with, a fibrosing composition; (f) constructingthe device itself, or a portion of the device, with a fibrosingcomposition; or (g) by covalently binding the fibrosing agent directlyto the device surface, or to a linker (small molecule or polymer) thatis coated or attached to the device surface. For these devices, thecoating process can be performed in such a manner as to (a) coat thesurfaces of the device that is in contact with the bone, (b) coat thesurfaces of the device that are not in contact with the bone or (c) coatall or parts of both the bone-contacting and non-bone contactingsurfaces of the device.

In addition to coating the spinal fusion device with the fibrosingcomposition, the fibrosis-inducing agent can be mixed with the materialsthat are used in the construction of the device such that the fibrosingagent is incorporated into the final device.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in spinal fusion devices (including fusionbaskets, fusion cage apparatus, interbody cages, interbody implants,fusion cage anchoring devices, fusion stabilization chamber, fusion cageanchoring plates; bone fixation devices including anchoring bone plates,bone screws, and other fixation hardware; and tissue fillers/implantsincluding bone cement, allograft material, autograft material, collagen,and other biocompatible tissue fillers) include talc, silk, wool,chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well asanalogues and derivatives of the aforementioned.

Optionally, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, and growth hormone) and/or a bone morphogenicprotein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or ananalogue or derivative thereof).

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

The administration and dosages of these agents for use in theseembodiments are described in section (vi) below.

(v) Intervertebral Disc Prostheses

In certain cases of DDD, the damaged vertebral segment may be treatedusing a intervertebral disc prosthesis that maintains vertebral anatomyand movement within the vertebral joint. This is often conducted whendamage to more than one vertebral segment occurs. As used herein, theterm “intervertebral disc prostheses” (or “artificial disc”) refers toimplants and/or devices that are located in, on, or near the spine andwhich enhance the ability of the spine to perform its function in thepatient. Examples of intervertebral disc prostheses include, withoutlimitation, artificial spinal discs and related devices includingvertebral implants, vertebral disc prostheses, lumbar disc implants,cervical disc implants, implantable intervertebral prostheses, spinalprostheses, artificial discs, prosthetic implants, prosthetic spinaldiscs, spinal disc endoprostheses, spinal implants, artificial spinaldiscs, intervertebral implants, implantable spinal grafts, artificiallumbar discs, spinal nucleus implants, and intervertebral disc spacers.

An artificial disc suitable for combining with a fibrosis-inducing agentaccording to the present invention may be composed of a single materialor several materials including, without limitation, allograft bonematerial (see e.g., U.S. Pat. No. 6,143,033), metals (see e.g., U.S.Pat. No. 4,955,908), and/or synthetic materials (see e.g., U.S. Pat.Nos. 6,264,695; 6,419,706; 5,824,093; and 4,911,718). The prosthesismust be biocompatible and may consist of biodegradable ornon-biodegradable components depending on the intended function of thedevice. See e.g., U.S. Pat. No. 4,772,287. The intervertebral discprosthesis may be biologically inert and serve as a mechanical means ofstabilizing the vertebral column (see e.g., U.S. Pat. Nos. 4,955,908 and5,716,415) or as a means of preserving spinal function. In anotheraspect, the prosthesis may be an alternative to spinal fusion. Theprosthesis may be a disc designed to provide normal movement betweenvertebral bone plates. The artificial disc may be intended to mimic thenatural shock absorbent function of the natural disc. The artificialdisc may be composed of a center core and end elements that support thedisc against the adjacent vertebra or it may be intended to replace onlya portion of the natural intervertebral disc (e.g., nucleus pulposus).For example, the artificial disc may be in the form of an elastomericsection sandwiched between two rigid plates. See e.g., U.S. Pat. Nos.6,162,252; 5,534,030; 5,017,437; and 5,031,437. The intervertebral discprosthesis may be an elongated prosthetic disc nucleus composed of ahydrogel core and a constraining flexible jacket that allows the core todeform and reform. See e.g., U.S. Pat. No. 5,824,093. The artificialdisc may be composed of a rigid superior and inferior concaval-convexelements and a nuclear body which is located between the concavesurfaces to permit movement. See e.g., U.S. Pat. No. 6,156,067. Theartificial disc may be a partial spinal prosthesis composed of a coremade of an elastic material such as silicone polymer or an elastomerwhich is covered by a casing made of a rigid material which is incontact with the adjacent vertebrae. See e.g., U.S. Pat. No. 6,419,706.The intervertebral disc prosthesis may replace only the nucleus pulposustissue by using a spinal nucleus implant comprised of a swellable,biomimetic plastic with a hydrophobic and hydrophilic phase which can beexpanded in situ to conform to the natural size and shape. See e.g.,U.S. Pat. No. 6,264,695. The artificial disc may be composed of acentral core formed from a biocompatible elastomer wrapped bymulti-layered laminae made from elastomer and fibers. See e.g., U.S.Pat. No. 4,911,718. The intervertebral disc prosthesis may be composedof a fluid-filled inner bladder with an outer layer of strong, inertfibers intermingled with a bioresorbable material which promotes tissueingrowth. See e.g., U.S. Pat. No. 4,772,287.

In one aspect, the present invention provides intervertebral discprostheses that include a fibrosis-inducing agent or a composition thatincludes a fibrosis-inducing agent to promote scarring and fixation ofthe device into the surrounding bone and yet retain the flexibility ofthe natural disc. In one aspect, an artificial disc is coated with afibrosis-inducing agent (or a composition that includes afibrosis-inducing agent) to enhance healing and the formation of fibroustissue similar to the annulus fibrosis. In another aspect, the fibrosingagent may be incorporated into the glue/cement that holds the artificialdisc in place. In another aspect, the intervertebral disc prosthesis iscovered (all or in part) with a silk mesh or lattice to encouragescarring and anchoring of the implant into the surrounding bone.

Numerous polymeric and non-polymeric carrier systems describedpreviously can be used to provide sustained release of thefibrosis-inducing agent from the artificial disc. Methods forincorporating fibrosing compositions onto or into intervertebral discprostheses include: (a) directly affixing to the device a fibrosingcomposition (e.g., by either a spraying process or dipping process asdescribed above, with or without a carrier); (b) directly incorporatinginto the device a fibrosing composition (e.g., by either a sprayingprocess or dipping process as described above, with or without acarrier); (c) by coating the device with a substance such as a hydrogelwhich can in turn absorb the fibrosing composition; (d) by interweavinga fibrosing composition (for example a silk strand or another polymericthread which releases a fibrosis-inducing agent) into the devicestructure; (e) by inserting the device into a sleeve or mesh which iscomprised of, or coated with, a fibrosing composition; (f) constructingthe device itself, or a portion of the device, with a fibrosingcomposition; or (g) by covalently binding the fibrosing agent directlyto the device surface, or to a linker (small molecule or polymer) thatis coated or attached to the device surface. For these devices, thecoating process can be performed in such a manner as to (a) coat thesurfaces of the device that is in contact with the vertebral bone, (b)coat the surfaces of the device that are not in contact with the bone or(c) coat all or parts of both the bone-contacting and non-bonecontacting surfaces of the device.

In addition to coating the artificial disc with the fibrosingcomposition, the fibrosing agent can be mixed with the materials thatare used to make the device such that the fibrosing agent isincorporated into the final prosthetic intervertebral disc.

In one embodiment, the therapeutic agent can be incorporated directlyinto the formulation (for example, direct incorporation of thefibrosis-inducing agent into the swellable, biomimetic polymers used tocreate an artificial nucleus pulposus tissue that expands in situ toconform to the natural size and shape of the intervertebral disc core).In another embodiment, the fibrosis-inducing agent can be incorporatedinto a secondary carrier (e.g., micelles, liposomes, emulsions,microspheres, nanospheres etc, as described above) that are then used inthe construction of, or as constituents of, an artificial disc.

It should be apparent to one of skill in the art that potentially anyfibrosis-inducing agents described above may be utilized alone, or incombination, in the practice of this embodiment. Exemplary fibrosingagents for use in spinal prostheses (e.g., devices and bulking agents)include talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin,and CTGF, as well as analogues and derivatives of the aforementioned.

Optionally, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, and growth hormone) and/or a bone hormone) and/or abone morphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6,or BMP-7 or an analogue or derivative thereof).

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

The administration and dosages of these agents for use in theseembodiments are described in section (vi) below.

(vi) Fibrosis-inducing Agents for Use in Spinal Conditions

As spinal prostheses and injectables are made in a variety ofconfigurations and sizes, the exact dose administered can vary with theamount injected or with the device size, surface area and design.However, certain principles can be applied in the application of thisart. Drug dose can be calculated as a function of dose per unit area (ofthe portion of the device being coated), total drug dose administeredcan be measured, and appropriate surface concentrations of active drugcan be determined. Regardless of the method of application of the drugto the spinal prostheses, the exemplary fibrosing agents, used alone orin combination, should be administered under the following dosingguidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered from a spinal prosthesis, or coatedonto the surface of a spinal prosthesis, should not exceed 100 mg (rangeof 1 μg to 100 mg). In one embodiment, the total amount of talc releasedfrom the prosthesis should be in the range of 10 μg to 50 mg. The doseper unit area of the device (i.e., the dosage of talc as a function ofthe surface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, talc should beapplied to a spinal prosthesis surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. In one embodiment, talc is released fromthe surface of a spinal prosthesis or from composition (e.g., a bulkingagent) such that fibrosis in the tissue is promoted for a period rangingfrom several hours to several months. Drug concentrations in a bulkingagent or other such material should be within the range described aboveexcept values are in mm³. For example, talc may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of talc (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as talc is administered at half the aboveparameters, a compound half as potent as talc is administered at twicethe above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered from a spinal prosthesis, or coatedonto the surface of a spinal prosthesis, should not exceed 100 mg (rangeof 1 μg to 100 mg). In one embodiment, the total amount of silk releasedfrom the prosthesis should be in the range of 10 μg to 50 mg. The doseper unit area of the device (i.e., the dosage of silk as a function ofthe surface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, silk should beapplied to a spinal prosthesis surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can release silk atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the spinal prosthesissuch that a minimum concentration of 0.01 nM to 1000 μM of silk isdelivered to the tissue. In one embodiment, silk is released from thesurface of a spinal prosthesis or from an injectable composition (e.g.,a bulking agent) such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example, silkmay be released in effective concentrations for a period ranging from 1hour-30 days. It should be readily evident given the discussionsprovided herein that analogues and derivatives of silk (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent assilk is administered at half the above parameters, a compound half aspotent as silk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered from a spinal prosthesis, or coatedonto the surface of a spinal prosthesis, should not exceed 100 mg (rangeof 1 μg to 100 mg). In one embodiment, the total amount of chitosanreleased from the prosthesis should be in the range of 10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of chitosan as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.05μg-10 μg per mm² of surface area coated. In another embodiment, chitosanshould be applied to a spinal prosthesis surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease chitosan at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from thespinal prosthesis such that a minimum concentration of 0.01 nM to 1000μM of chitosan is delivered to the tissue. In one embodiment, chitosanis released from the surface of a spinal prosthesis or from aninjectable composition (e.g., a bulking agent) such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, chitosan may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of chitosan (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as chitosan is administered at halfthe above parameters, a compound half as potent as chitosan isadministered at twice the above parameters, etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered from a spinal prosthesis, orcoated onto the surface of a spinal prosthesis, should not exceed 100 mg(range of 1 μg to 100 mg). In one embodiment, the total amount ofpolylysine released from the prosthesis should be in the range of 10 μgto 50 mg. The dose per unit area of the device (i.e., the dosage ofpolylysine as a function of the surface area of the portion of thedevice to which drug is applied and/or incorporated) should fall withinthe range of 0.05 μg-10 μg per mm² of surface area coated. In anotherembodiment, polylysine should be applied to a spinal prosthesis surfaceat a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificmedical devices can release polylysine at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the spinal prosthesis such that a minimumconcentration of 0.01 nM to 1000 μM of polylysine is delivered to thetissue. In one embodiment, polylysine is released from the surface of aspinal prosthesis or from a composition (e.g., a bulking agent) suchthat fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, polylysine may be releasedin effective concentrations for a period ranging from 1 hour-30 days. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of polylysine (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as polylysine isadministered at half the above parameters, a compound half as potent aspolylysine is administered at twice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered from a spinalprosthesis, or coated onto the surface of a spinal prosthesis, shouldnot exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, thetotal amount of fibronectin released from the prosthesis should be inthe range of 10 μg to 50 mg. The dose per unit area of the device (i.e.,the dosage of fibronectin as a function of the surface area of theportion of the device to which drug is applied and/or incorporated)should fall within the range of 0.05 μg-10 μg per mm² of surface areacoated. In another embodiment, talc should be applied to a spinalprosthesis surface at a dose of 0.05 μg/mm²-10 μg/mm² of surface areacoated. As specific (polymeric and non-polymeric) drug delivery vehiclesand specific medical devices can release fibronectin at differing rates,the above dosing parameters should be utilized in combination with therelease rate of the drug from the spinal prosthesis such that a minimumconcentration of 0.01 nM to 1000 μM of fibronectin is delivered to thetissue. In one embodiment, fibronectin is released from the surface of aspinal prosthesis or from a composition (e.g., a bulking agent) suchthat fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, fibronectin may bereleased in effective concentrations for a period ranging from 1 hour-30days. It should be readily evident given the discussions provided hereinthat analogues and derivatives of fibronectin (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as fibronectin isadministered at half the above parameters, a compound half as potent asfibronectin is administered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered from a spinal prosthesis, orcoated onto the surface of a spinal prosthesis, should not exceed 100 mg(range of 0.01 μg to 100 mg). In one embodiment, the total amount ofbleomycin released from the prosthesis should be in the range of 0.10 μgto 50 mg. The dose per unit area of the device (i.e., the dosage ofbleomycin as a function of the surface area of the portion of the deviceto which drug is applied and/or incorporated) should fall within therange of 0.005 μg-10 μg per mm² of surface area coated. In anotherembodiment, bleomycin should be applied to a spinal prosthesis surfaceat a dose of 0.005 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificmedical devices can release bleomycin at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the spinal prosthesis such that a minimumconcentration of 0.001 nM to 1000 μM of bleomycin is delivered to thetissue. In one embodiment, bleomycin is released from the surface of aspinal prosthesis or from a composition (e.g., a bulking agent) suchthat fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, bleomycin may be releasedin effective concentrations for a period ranging from 1 hour-30 days. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of bleomycin (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as bleomycin isadministered at half the above parameters, a compound half as potent asbleomycin is administered at twice the above parameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered from a spinal prosthesis, or coatedonto the surface of a spinal prosthesis, should not exceed 100 mg (rangeof 0.01 μg to 100 mg). In one embodiment, the total amount of CTGFreleased from the prosthesis should be in the range of 0.10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of CTGF as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.005μg-10 μg per mm² of surface area coated. In another embodiment, CTGFshould be applied to a spinal prosthesis surface at a dose of 0.005μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease CTGF at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from thespinal prosthesis such that a minimum concentration of 0.001 nM to 1000μM of CTGF is delivered to the tissue. In one embodiment, CTGF isreleased from the surface of a spinal prosthesis or from a composition(e.g., a bulking agent) such that fibrosis in the tissue is promoted fora period ranging from several hours to several months. For example, CTGFmay be released in effective concentrations for a period ranging from 1hour-30 days. It should be readily evident given the discussionsprovided herein that analogues and derivatives of CTGF (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asCTGF is administered at half the above parameters, a compound half aspotent as CTGF is administered at twice the above parameters, etc.).

As described above, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, and growth hormone) and/or a bone morphogenicprotein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or ananalogue or derivative thereof.

Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof) are to be used informulations at concentrations that range from 0.001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the bone morphogenic protein is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.001μg to 500 mg); preferred 1 μg to 250 mg. When used as a device coating,the dose is per unit area of 0.001 μg-1000 μg per mm²; with a preferreddose of 0.01 μg/mm²-200 μg/mm². Minimum concentration of 10⁻⁹-10⁻⁴ M ofbone morphogenic protein is to be maintained on the device surface.

Inflammatory cytokines are to be used in formulations at concentrationsthat range from 0.0001 μg/ml to approximately 20 mg/ml depending on thespecific clinical application, formulation type (e.g., gel, liquid,solid, semi-solid), formulation chemistry, duration of requiredapplication, type of medical device interface and formulation volume andor surface area coverage required. Preferably, the inflammatory cytokineis released in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see Example 16). The proliferative agents are to beused in formulations at concentrations that range from 0.1 ng/ml to 25mg/ml depending on the specific clinical application, formulation type(e.g., gel, liquid, solid, semi-solid), formulation chemistry, durationof required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention. Briefly then,some aspects of the present invention are: a method comprisingintroducing into an intervertebral disc space of a patient in needthereof, a therapeutically effective amount of a fibrosing agent or acomposition comprising a fibrosing agent, where the fibrosing agentinduces a fibrotic response at the intervertebral disc space of thepatient, thereby providing the patient with a beneficial result.Optionally, any one or more of the following criteria may be used todescribe this aspect of the invention: the beneficial result is therepair of a spinal disc; the beneficial result is fibrous ankylosis; thebeneficial result is bony ankylosis; the agent promotes regeneration;the agent promotes angiogenesis; the agent promotes fibroblastmigration; the agent promotes fibroblast proliferation; the agentpromotes deposition of extracellular matrix (ECM); the agent promotesremodeling, i.e., the maturation and organization of fibrous tissue; theagent is an arterial vessel wall irritant; the fibrosing agent is orcomprises silk; the fibrosing agent is or comprises silkworm silk; thefibrosing agent is or comprises spider silk; the fibrosing agent is orcomprises recombinant silk; the fibrosing agent is or comprises rawsilk; the fibrosing agent is or comprises hydrolyzed silk; the fibrosingagent is or comprises acid-treated silk; the fibrosing agent is orcomprises acylated silk; the fibrosing agent is in the form of strands;the fibrosing agent is in the form of tufts; the fibrosing agent is inthe form of microparticulates; the fibrosing agent is or comprisesmineral particles; the fibrosing agent is or comprises talc; thefibrosing agent is or comprises chitosan; the fibrosing agent is orcomprises polylysine; the fibrosing agent is or comprises fibronectin;the fibrosing agent is or comprises bleomycin; the fibrosing agent is orcomprises CTGF; the fibrosing agent is in the form of a thread, or is incontact with a thread where, optionally, the thread is biodegradable(e.g., it comprises a material selected from the group consisting ofpolyester, polyanhydride, poly(anhydride ester), poly(ester-amide),poly(ester-urea), polyorthoester, polyphosphoester, polyphosphazine,polycyanoacrylate, collagen, chitosan, hyaluronic acid, chromic cat gut,alginate, starch, cellulose and cellulose ester) or the thread isnon-biodegradable (e.g., it comprises a material selected from the groupconsisting of polyester, polyurethane, silicone, polyethylene,polypropylene, polystyrene, polyacrylate, polymethacrylate, and silk),the thread is coated with a polymer, the thread is coated with apharmaceutical agent that induces a fibrotic response in the patient,the thread is coated with a pharmaceutical agent that induces anosteogenic response in the patient; the composition further comprises anagent that promotes bone growth; the agent that promotes bone growth isa bone morphogenic protein or the agent that promotes bone growth is anosteogenic growth factor (e.g., transforming growth factor,platelet-derived growth factor, and fibroblast growth factor); thecomposition further comprises a pharmaceutical agent that inducessclerosis (a sclerosant, e.g., a sclerosant is selected from the groupconsisting of ethanol, dimethyl sulfoxide, sucrose, sodium chloride,dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol,sodium tetradecyl sulfate, sodium morrhuate, and sotradecol, or thesclerosant may be a surfactant); the composition further comprises aninflammatory cytokine (e.g., an inflammatory cytokine selected from thegroup consisting of TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a,IL-1, IL-1-β, IL-8, IL-6, and growth hormone); the composition furthercomprises an agent that stimulates cell proliferation (e.g., a cellproliferation agent selected from the group consisting of dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof);the composition further comprises a bulking agent; the compositionfurther comprises a sealant; the composition further comprises apolymeric carrier; the composition further comprises a resorbableceramic; the composition further comprises a contrast agent; thecomposition further comprises a thread; the composition is in the formof a gel; the composition is in the form of a paste; the composition isin the form of a spray; the composition is in the form of an aerosol;the composition is in the form of a suspension; the composition is inthe form of an emulsion or microemulsion; the composition is in the formof a microsphere; the composition is in the form of a microparticulate;the composition is in the form of a solid implant.

2. Joint Implants

The present invention provides for the combination of afibrosis-inducing agent and a prosthetic joint implant. As used herein,the term “joint implants” refer to implants that are designed to replacejoints that have been physically impaired or damaged. Examples of jointimplants include, without limitation, orthopedic implants, orthopedicprostheses, modular implants, prosthetic joints, modular prostheses,joint prostheses, partial prostheses, hip implants, knee implants,shoulder implants and digit implants. Other types of orthopedic implantsthat may be used in conjunction with joint implants include, e.g.,hardware, such as internal and external fixation devices, pins, platesand screws.

In one aspect, the orthopedic implant is an internal fixation implant.Internal fixation implants are medical devices that can be implanted(usually permanently) into a patient in minimally invasive orthopedicreconstructions and are often indicated for immobilization andstabilization of extremity fractures and unstable fractures.

Representative examples of internal fixation implants includeintramedullary fixation devices such as intermedullary nails and plateand screw combinations; intramedullary rods, vertical transarticularpins for stabilization of severe ankle fractures, plates (e.g., platesmade from titanium, stainless steel, and the like), plates with prongsto support subchondral bone, dorsal plates for volar applications,elastic plates, screws, clips, pins, staples, pegs, wires, sublaminarwires, and metal prostheses for holding vertebrae in place.

Internal fixation implants may be used in a variety of open reductioninternal fixation (ORIF) procedures. Open reduction internal fixation isa method of surgically repairing a fractured bone that typicallyinvolves either the use of plates and screws or an intramedullary (IM)rod to align and stabilize fractures. For example, IM rods can beinserted into the bone marrow canal in the center of the long bones ofthe extremities (e.g., femur or tibia).

In another aspect, the orthopedic implant is a component (e.g., a pin,wire, stopper, or dowel) of an external fixation device or an implantedportion (i.e., a portion that is situated within the body of thepatient) of an external fixation device (also referred to herein as an“external fixation implant”). External fixation devices are medicaldevices that can be used to immobilize bones to allow a fracture toheal. External fixation devices are used in a variety of minimallyinvasive orthopedic surgeries as an alternative to other types offixation devices, such as casts and internal fixation devices.

Briefly, external fixation may be accomplished by placing pins or screwsinto the bone on both sides of the fracture. The pins are then securedtogether outside the skin with clamps and rods which can form anexternal frame.

An external fixation device typically includes a scaffold or frame thathas attached to it wires, pins, and the like which is placed outside ofan extremity, such as a limb. The device remains in place until healinghas occurred, at which point it is then removed, leaving no foreignmaterial in the extremity.

External fixation devices may take a variety of forms and may havemonolateral, multiplanar or hybrid constructions. A monolateral fixationdevice includes a bar or rail with attached pins that transfix a bone(e.g., a femur). A multiplanar external fixation device can includerings or sections of rings, with attached pins and/or wires, which areused to secure fixation of a bone. A hybrid system can include a frameconsisting of both rings (multiplanar) and bars (monolateral).

External fixation devices also may be classified by their function, forexample, the device may be stationary or moving. Stationary devices maybe used for alignment of the bony fragments (e.g., for acutestabilization of fractures) and remain in place from the time ofapplication to removal. Moving fixation devices, in contrast, may beused in gradual reduction of acute extremity fractures. Theconfiguration of a moving fixation device can change over time forgradual correction.

External fixation devices may be used to treat a variety of conditions.For example, an external fixation device may be used for the fixation ofinjuries such as joint fractures. External fixation can provide foracute or gradual fracture reduction. In particular, external fixationdevices may be used in the treatment of juxta-articular fractures, openfractures, and fractures with bone loss, including, for example,fractures near joints such as distal radius, proximal tibial plateau,and distal tibial pilon fractures. Other applications of externalfixation devices include reconstructive orthopedic procedures such astreatment of deformities, bone loss, contractures, treatment ofnon-unions (hypertrophic or atrophic), and limb length discrepancy.

A modular prosthesis is a prosthesis that has multiple (two or more)components, which can be assembled to form a unitary biomechanicalstructure. Various features of the components can be adjusted by thesurgeon prior to implantation of the prosthesis so as to accommodate theneeds of each patient. For example, a modular prosthesis can havecomponent that can be independently adjusted (rotationally and axially)by the surgeon, or the length of a component may be changed. Modularprostheses can be used in a variety of surgical procedures. The modularprosthesis may be an adjustable long bone prosthesis that can beadjusted within the patient to account for discrepancies in themeasurement of a long bone to be replaced. Prosthetic joints havingmodular components exist for replacement of the hip, knee, and anklejoints. Other representative examples of modular orthopedic prosthesesinclude a modular femoral stem, modular shoulder prosthesis, and modularelbow prostheses.

The long-term cause of failure for many artificial joints is looseningoccurring over time between the implant and the surrounding bone thatanchors the implant in place. Inadequate bone and tissue growth may leadto unsuccessful acute incorporation of the implant or late loosening mayoccur with time. In the case of the hip, for example, up to 5% ofpatients can suffer from joint loosening by 10 years post implant.Symptoms include pain that can become debilitating and ultimately leadto repeat surgery and possible revision of the implant.

(i) Hip Implants

In artificial hip joints, the hip implant replaces the head of femur(i.e., ball) and/or the acetabulum (i.e., socket) of the joint.Typically the hip joint is replaced due to irreparable damage caused bynon-inflammatory degenerative joint disease (e.g., osteoarthritis, posttraumatic arthritis), inflammatory degenerative joint disease (e.g.,rheumatoid arthritis, infectious arthritis), trauma (e.g., fracture ofthe pelvis or hip), congenital hip dysplasia, or joint dislocation andother fracture-induced damage to the femur and/or acetabulum. Hipimplants typically include two or three component systems, which includethe femoral stem or shank, the femoral neck, and the spherical ballwhich adapts to the acetabulum or prosthetic acetabular cup. The femoralstem, neck and ball, as well as the acetabular cup may be composed ofmetal (e.g., titanium, titanium alloy, cobalt-chromium orchromium-molybdenum) or polymer composite. To fix the hip implant to theexisting femur of the host, the hip implant may be cemented into thebone using bone cement (e.g., methylmethacrylate) or the hip implant maybe fixed using a cementless surface treatment (e.g., porous coating,such as hydroxyapatite porous coating, or spongy coating) whereby thehip implant allows bony growth from the femur to anchor it into place.

In one aspect, hip implants may be used to provide a full hipreplacement. For example, the hip implant may be a three-modulardesigned total prosthesis with primary fixation, which may include apartially threaded elongated pin for insertion into the femoral body,which provides rotational adjustment between the body and the pin forvarious alignments and size combinations. See e.g., U.S. Pat. No.4,938,773. The hip implant may be composed of a ball, neck and fixationelement with a bearing element that is adapted to restrain dislocationsof the ball and provide a means for selecting the orientation of thefixation element. See e.g., U.S. Pat. No. 6,042,611. The hip implant maybe designed of two mutually articulating components composed of a cobaltchromium alloy with one having a low carbon content and the othercomponent having a high carbon content. See e.g., U.S. Pat. No.5,904,720.

In another aspect, hip implants may be adapted for cementing into placeto ensure the implant is stabilized in the accurate position. Forexample, hip implants may be composed of cement spacers along the shaftwhich, upon implantation within the medullary canal of the femur, allowsfor optimal thickness of the cement mantle. See e.g., U.S. Pat. No.5,314,489.

In another aspect, hip implants may be modular in which components maybe adjusted to adapt to the host's shape or dimensions. For example, thehip implant may be a modular hip prosthesis composed of a plurality ofremovable, different size tubular sleeves that may be used to extend thefemoral stem component or neck size which allows the implant to becustom fitted to a particular host. See e.g., U.S. Pat. No. 5,507,830.

In another aspect, hip implants may be designed to provide shockabsorbency within the joint. For example, the hip implant may becomposed of an elongate element that extends coaxially from the ballsection that slidably extends into a chamber that contains a spring forshock absorbency. See e.g., U.S. Pat. No. 5,389,107. The hip implant maybe a modular shock absorbent prosthesis designed to have adjustablefemoral stem, neck and ball, as well as adjustable tension due to itsunique coupling modular spring mechanism. See e.g., U.S. Pat. No.6,336,941.

In another aspect, hip implants may be composed of a composite materialto provide greater stiffness or retention within the femur. For example,the hip implant may be composed of a plurality of layers of fibers(e.g., composed of carbon, ceramic, metal or fiberglass) in a matrix(e.g., a polymeric matrix) where the fibers may be substantiallyunidirectional in each respective layer. See e.g., U.S. Pat. Nos.5,522,904, 5,163,962, 5,064,439 and 4,892,552. The hip implant may havea stem composed of an inner metal core and an outer composite shellhaving fibers bonded with a thermoplastic resin and which the distal endis adapted to be inserted into a cavity formed in a bone. See e.g., U.S.Pat. No. 5,314,492. The hip implant may be composed of an expandablematerial that absorbs body fluid and expands within an opening of thebone of the host's body such that a portion of the implant is retainedwithin the bone and a portion of the implant is outside the bone. Seee.g., U.S. Pat. No. 6,361,565.

In another aspect, hip implants may be only partial hip replacements.For example, the hip implant may be a prosthetic acetabular cup assemblybeing composed of a bearing component for receiving a ball attached to afemur and a shell component for attachment to an acetabulum. See e.g.,U.S. Pat. No. 5,049,158. Still other hip implants may be revision hipprostheses which have design features to augment the fixation of theimplant into an area with bone-deficiency. For example, the hip implantmay be a long stem hip joint prosthetic device having a long distalsection of the femoral component which extends beyond the isthmus of thefemur when implanted in the medullary canal and is designed with aspecially curved distal section. See e.g., U.S. Pat. No. 4,871,369.Additional descriptions of hip implants are provided in U.S. Pat. Nos.5,755,810; 5,336,265; 5,286,260; 5,019,108; 4,986,834; 4,808,186; and4,670,015.

Hip implants, which may be combined with one or more drugs according tothe present invention, include numerous commercially available products,for example, the S—ROM Total Hip System and the AML Total Hip Systemfrom DePuy Orthopaedics, Inc. (Warsaw, Ind.).

In one aspect, the present invention provides hip prostheses thatinclude a fibrosis-inducing agent or a composition that includes afibrosis-inducing agent to promote scarring to provide fixation of thedevice into the surrounding bone. In one aspect, the hip prosthesis iscoated with a fibrosing agent or a composition that includes thefibrosing agent. In another aspect, the fibrosing agent may beincorporated into a glue or cement that holds the prosthesis in place.In another aspect, the hip prosthesis is covered (all or in part) with asilk mesh or lattice to encourage scarring and anchoring into thesurrounding bone. For example, a silk mesh or lattice can be coated ontoall or a portion of the surface of the implant stem to encouragescarring and anchoring into the surrounding bone.

Numerous polymeric and non-polymeric carrier systems describedpreviously can be used in the practice of this embodiment. Thesecompositions can further include one or more fibrosis-inducing agents topromote the formation of granulation tissue. Methods for incorporatingfibrosing compositions onto or into the orthopedic implants include: (a)directly affixing to the device a fibrosing composition (e.g., by eithera spraying process or dipping process as described above, with orwithout a carrier); (b) directly incorporating into the device afibrosing composition (e.g., by either a spraying process or dippingprocess as described above, with or without a carrier); (c) by coatingthe device with a substance such as a hydrogel which can in turn absorbthe fibrosing composition; (d) by interweaving fibrosing compositioncoated thread (or the polymer itself formed into a thread) into thedevice structure; (e) by inserting the device into a sleeve or meshwhich is comprised of or coated with a fibrosing composition; (f)constructing the device itself or a portion of the device with afibrosing composition; and/or (g) by covalently binding the fibrosingagent directly to the device surface or to a linker (small molecule orpolymer) that is coated or attached to the device surface. For thesedevices, the coating process can be performed in such a manner as to a)coat the surfaces of the device that is in contact with the bone, b)coat the surfaces of the device that are not in contact with the bone orc) coat all or parts of both the bone-contacting and non-bone contactingsurface of the device.

In addition to coating the device with the fibrosing composition, thefibrosing agent can be mixed with the materials that are used to makethe device such that the fibrosing agent is incorporated into the finaldevice.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described previously may beutilized alone, or in combination, in the practice of this embodiment.Exemplary fibrosing agents for use in hip prostheses implants includetalc, silk, wool, chitosan, polylysine, fibronectin, bleomycin, andCTGF, as well as analogues and derivatives of the aforementioned.

As hip prostheses are made in a variety of configurations and sizes, theexact dose administered can vary with device size, surface area anddesign. However, certain principles can be applied in the application ofthis art. Drug dose can be calculated as a function of dose per unitarea (of the portion of the device being coated), total drug doseadministered can be measured and appropriate surface concentrations ofactive drug can be determined. Regardless of the method of applicationof the drug to the hip prostheses, the exemplary fibrosing agents, usedalone or in combination, should be administered under the followingdosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered from a hip prosthesis, or coated ontothe surface of a hip prosthesis, should not exceed 100 mg (range of 1 μgto 100 mg). In one embodiment, the total amount of talc released fromthe prosthesis should be in the range of 10 μg to 50 mg. The dose perunit area of the device (i.e., the dosage of talc as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, talc should beapplied to a hip prosthesis surface at a dose of 0.05 μg/mm²-10 μg/mm²of surface area coated. In one embodiment, talc is released from thesurface of a hip prosthesis such that fibrosis in the tissue is promotedfor a period ranging from several hours to several months. For example,talc may be released in effective concentrations for a period rangingfrom 1 hour-30 days. It should be readily evident given the discussionsprovided herein that analogues and derivatives of talc (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent astalc is administered at half the above parameters, a compound half aspotent as talc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered from a hip prosthesis, or coated ontothe surface of a hip prosthesis, should not exceed 100 mg (range of 1 μgto 100 mg). In one embodiment, the total amount of silk released fromthe prosthesis should be in the range of 10 μg to 50 mg. The dose perunit area of the device (i.e., the dosage of silk as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, silk should beapplied to a hip prosthesis surface at a dose of 0.05 μg/mm²-10 μg/mm²of surface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific medical devices can release silk atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the hip prosthesissuch that a minimum concentration of 0.01 nM to 1000 μM of silk isdelivered to the tissue. In one embodiment, silk is released from thesurface of a hip prosthesis such that fibrosis in the tissue is promotedfor a period ranging from several hours to several months. For example,silk may be released in effective concentrations for a period rangingfrom 1 hour-30 days. It should be readily evident given the discussionsprovided herein that analogues and derivatives of silk (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent assilk is administered at half the above parameters, a compound half aspotent as silk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered from a hip prosthesis, or coatedonto the surface of a hip prosthesis, should not exceed 100 mg (range of1 μg to 100 mg). In one embodiment, the total amount of chitosanreleased from the prosthesis should be in the range of 10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of chitosan as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.05μg-10 μg per mm² of surface area coated. In another embodiment, chitosanshould be applied to a hip prosthesis surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease chitosan at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from thehip prosthesis such that a minimum concentration of 0.01 nM to 1000 μMof chitosan is delivered to the tissue. In one embodiment, chitosan isreleased from the surface of a hip prosthesis such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, chitosan may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of chitosan (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as chitosan is administered at halfthe above parameters, a compound half as potent as chitosan isadministered at twice the above parameters, etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered from a hip prosthesis, or coatedonto the surface of a hip prosthesis, should not exceed 100 mg (range of1 μg to 100 mg). In one embodiment, the total amount of polylysinereleased from the prosthesis should be in the range of 10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of polylysine asa function of the surface area of the portion of the device to whichdrug is applied and/or incorporated) should fall within the range of0.05 μg-10 μg per mm² of surface area coated. In another embodiment,polylysine should be applied to a hip prosthesis surface at a dose of0.05 μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease polylysine at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe hip prosthesis such that a minimum concentration of 0.01 nM to 1000μM of polylysine is delivered to the tissue. In one embodiment,polylysine is released from the surface of a hip prosthesis such thatfibrosis in the tissue is promoted for a period ranging from severalhours to several months. For example, polylysine may be released ineffective concentrations for a period ranging from 1 hour-30 days. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of polylysine (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as polylysine isadministered at half the above parameters, a compound half as potent aspolylysine is administered at twice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered from a hip prosthesis,or coated onto the surface of a hip prosthesis, should not exceed 100 mg(range of 1 μg to 100 mg). In one embodiment, the total amount offibronectin released from the prosthesis should be in the range of 10 μgto 50 mg. The dose per unit area of the device (i.e., the dosage offibronectin as a function of the surface area of the portion of thedevice to which drug is applied and/or incorporated) should fall withinthe range of 0.05 μg-10 μg per mm² of surface area coated. In anotherembodiment, fibronectin should be applied to a hip prosthesis surface ata dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificmedical devices can release fibronectin at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the hip prosthesis such that a minimumconcentration of 0.01 nM to 1000 μM of fibronectin is delivered to thetissue. In one embodiment, fibronectin is released from the surface of ahip prosthesis such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, fibronectinmay be released in effective concentrations for a period ranging from 1hour-30 days. It should be readily evident given the discussionsprovided herein that analogues and derivatives of fibronectin (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asfibronectin is administered at half the above parameters, a compoundhalf as potent as fibronectin is administered at twice the aboveparameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered from a hip prosthesis, or coatedonto the surface of a hip prosthesis, should not exceed 100 mg (range of0.01 μg to 100 mg). In one embodiment, the total amount of bleomycinreleased from the prosthesis should be in the range of 0.10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of bleomycin as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.005μg-10 μg per mm² of surface area coated. In another embodiment,bleomycin should be applied to a hip prosthesis surface at a dose of0.005 μg/mm²-10 μg/mm² of surface area coated. As specific (polymericand non-polymeric) drug delivery vehicles and specific medical devicescan release bleomycin at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe hip prosthesis such that a minimum concentration of 0.001 nM to 1000μM of bleomycin is delivered to the tissue. In one embodiment, bleomycinis released from the surface of a hip prosthesis such that fibrosis inthe tissue is promoted for a period ranging from several hours toseveral months. For example, bleomycin may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of bleomycin (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as bleomycin is administered at halfthe above parameters, a compound half as potent as bleomycin isadministered at twice the above parameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered from a hip prosthesis, or coated ontothe surface of a hip prosthesis, should not exceed 100 mg (range of 0.01μg to 100 mg). In one embodiment, the total amount of CTGF released fromthe prosthesis should be in the range of 0.10 μg to 50 mg. The dose perunit area of the device (i.e., the dosage of CTGF as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.005 μg-10 μg permm² of surface area coated. In another embodiment, CTGF should beapplied to a hip prosthesis surface at a dose of 0.005 μg/mm²-10 μg/mm²of surface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific medical devices can release CTGF atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the hip prosthesissuch that a minimum concentration of 0.001 nM to 1000 μM of CTGF isdelivered to the tissue. In one embodiment, CTGF is released from thesurface of a hip prosthesis such that fibrosis in the tissue is promotedfor a period ranging from several hours to several months. For example,CTGF may be released in effective concentrations for a period rangingfrom 1 hour-30 days. It should be readily evident given the discussionsprovided herein that analogues and derivatives of CTGF (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asCTGF is administered at half the above parameters, a compound half aspotent as CTGF is administered at twice the above parameters, etc.).

Optionally, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, and growth hormone) and/or a bone morphogenicprotein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or ananalogue or derivative thereof).

Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof) are to be used informulations at concentrations that range from 0.001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the bone morphogenic protein is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.001μg to 500 mg); preferred 1 μg to 250 mg. When used as a device coating,the dose is per unit area of 0.001 μg-1000 μg per; with a preferred doseof 0.01 μg/mm²-200 μg/mm². Minimum concentration of 10⁻⁹-10⁻⁴ M of bonemorphogenic protein is to be maintained on the device surface.

Inflammatory cytokines are to be used in formulations at concentrationsthat range from 0.0001 μg/ml to approximately 20 mg/ml depending on thespecific clinical application, formulation type (e.g., gel, liquid,solid, semi-solid), formulation chemistry, duration of requiredapplication, type of medical device interface and formulation volume andor surface area coverage required. Preferably, the inflammatory cytokineis released in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D_(3,) diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see Example 16). The proliferative agents are to beused in formulations at concentrations that range from 0.1 ng/ml to 25mg/ml depending on the specific clinical application, formulation type(e.g., gel, liquid, solid, semi-solid), formulation chemistry, durationof required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

(ii) Knee Implants

In one aspect, the present invention provides knee implants that inducefibrosis or adhesion of the implant into the surrounding tissue. Kneereplacement surgery is generally indicated for patients with severe kneepain and disability caused by damage to their articular cartilage as aresult of rheumatoid arthritis, osteoarthritis or trauma. It is highlysuccessful procedure in relieving pain and restoring joint function.Knee arthroplasty procedures are broadly categorized as primary orrevision and are either unicompartmental (partial) or total. Kneeprostheses (referred to herein as knee implants) can be used to replaceall or a portion of the knee joint. In a total knee arthroplasty (TKA),the diseased cartilage surfaces of the thighbone (femur), the shinbone(tibia) and the kneecap (patella) are replaced by prostheses made ofmetal alloys (e.g., titanium- or cobalt/chromium-based alloys) andhigh-grade plastics and polymeric materials (e.g., ultrahigh-densitypolyethylene). Most of the other structures of the knee, such as theconnecting ligaments, remain intact. Up to three bone surfaces may bereplaced during a TKA: the distal ends (condyles) of the femur, theproximal surface of the tibia and the posterior surface of the patella.Components are designed so that metal always articulates againstplastic, which provides smooth movement and results in minimal wear.

Knee joint implants typically have three components (i.e., a femoral, atibial, and a patellar component). The metal femoral component curvesaround the end of the thighbone and has an interior groove so thepatella can move up and down smoothly against the bone as the knee bendsand straightens. Usually, one large piece is used to resurface the endof the bone. If only one condyle of the femur is damaged, a smallerpiece may be used (unicompartmental knee replacement) to resurface justthat part of the bone. Some designs (e.g., posterior stabilized designs)have an internal post with a circular-shaped device (cam) that workswith a corresponding tibial component to help prevent the femur fromsliding forward too far on the tibia when the knee is bent. The tibialcomponent is a flat metal platform with a polyethylene cushion. Thecushion may be part of the platform (fixed) or separate (mobile) witheither a flat surface (PCL-retaining) or a raised, sloping surface(PCL-substituting). The patellar component is a dome-shaped piece ofpolyethylene that duplicates the shape of the kneecap anchored to a flatmetal plate. Once the knee prosthesis is implanted and aligned, the kneereplacement is fixed in place by cement, using a cementless procedure,or via a hybrid fixation procedure.

A variety of knee prostheses have been described. For example, kneeprostheses have been described in U.S. Pat. Nos. 6,443,991; 6,402,786;6,068,658; 6,558,427; 6,554,866; 6,447,549; 6,419,707; 6,143,034;6,120,546; and 6,074,424. Knee implants suitable for combining with oneor more fibrosis-inducing agents according to the present invention,include numerous commercially available products. These include, forexample, the NEXGEN LEGACY Knee Posterior Stabilized (LPS) and NEXGENLEGACY LPS Femoral Component from Zimmer. Other examples of kneeimplants suitable for the delivery of fibrosis-inducing agents includeStryker Howmedica Osteonics DURACON Total Knee System, SCORPIO KneeSystem, and SCORPIO Cruciate Retaining Single Axis Knee; implantsavailable from DePuy Orthopaedics such as the LCS Total Knee System,P.F.C. Sigma RP Platform Knee System, Keane Uni-Compartmental KneeSystem, P.F.C. Sigma Uni-Compartmental Knee System, AMK Total KneeSystem, P.F.C. Sigma Knee System (Cruciate-Retaining), the P.F.C. SigmaKnee System (Cruciate-Substituting), the Coordinate Revision KneeSystem, the P.F.C. Sigma Knee System TC3 Revision implant, and the S-ROMNoiles Rotating Hinge; knee implants from Smith & Nephew Orthopaedicssuch as the GENESID I and GENESIS II Total Knee Systems. Othermanufacturers of primary and revision knee joint implants suitable foruse in this invention include Biomet, Inc. (Warsaw, Ind.), SulzerOrthopedics, Inc. (Austin, Tex.), Wright Medical Technologies, Exactech,Inc., Encore Orthopedics Corporation (Henderson, Nev.), Implex now knownas Zimmer, Inc., StelKast Company (McMurray, Pa.), Hayes Medical, Inc.(El Dorado Hills, Calif.), and Link Orthopedics (PineBrook, N.J.).

In one aspect, the present invention provides knee prostheses thatinclude a fibrosis-inducing agent or a composition that includes afibrosis-inducing agent to promote scarring and fixation of the deviceinto the surrounding bone. In one aspect, the knee prosthesis is coatedwith a fibrosing agent or a composition that includes the fibrosingagent. In another aspect, the fibrosing agent may be incorporated intothe glue or cement that holds the prosthesis in place. In anotheraspect, the knee prosthesis is covered (all or in part) with a silk meshor lattice to encourage scarring and anchoring into the surroundingbone. For example, a silk mesh or lattice can be coated onto all or aportion of the surface of the implant stem to encourage scarring andanchoring into the surrounding bone.

Numerous polymeric and non-polymeric carrier systems described above canbe used in the practice of this embodiment. These compositions canfurther include one or more fibrosis-inducing agents to promote theformation of granulation tissue. Methods for incorporating fibrosingcompositions onto or into the orthopedic implants include: (a) directlyaffixing to the device a fibrosing composition (e.g., by either aspraying process or dipping process as described above, with or withouta carrier); (b) directly incorporating into the device a fibrosingcomposition (e.g., by either a spraying process or dipping process asdescribed above, with or without a carrier); (c) by coating the devicewith a substance such as a hydrogel which can in turn absorb thefibrosing composition; (d) by interweaving fibrosing composition coatedthread (or the polymer itself formed into a thread) into the devicestructure; (e) by inserting the device into a sleeve or mesh which iscomprised of or coated with a fibrosing composition; (f) constructingthe device itself or a portion of the device with a fibrosingcomposition, or (g) by covalently binding the fibrosing agent directlyto the device surface or to a linker (small molecule or polymer) that iscoated or attached to the device surface. For these devices, the coatingprocess can be performed in such a manner as to a) coat the surfaces ofthe device that is in contact with the bone, b) coat the surfaces of thedevice that are not in contact with the bone or c) coat all or parts ofboth the bone-contacting and non-bone contacting surface of the device.

In addition to coating the device with the fibrosing composition, thefibrosing agent can be mixed with the materials that are used to makethe device such that the fibrosing agent is incorporated into the finaldevice.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in knee prostheses include talc, silk, wool,chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well asanalogues and derivatives of the aforementioned.

As knee prostheses are made in a variety of configurations and sizes,the exact dose administered can vary with device size, surface area anddesign. However, certain principles can be applied in the application ofthis art. Drug dose can be calculated as a function of dose per unitarea (of the portion of the device being coated), total drug doseadministered can be measured and appropriate surface concentrations ofactive drug can be determined. Regardless of the method of applicationof the drug to the knee prostheses, the exemplary fibrosing agents, usedalone or in combination, should be administered under the followingdosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered from a knee prosthesis, or coated ontothe surface of a knee prosthesis, should not exceed 100 mg (range of 1μg to 100 mg). In one embodiment, the total amount of talc released fromthe prosthesis should be in the range of 10 μg to 50 mg. The dose perunit area of the device (i.e., the dosage of talc as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, talc should beapplied to a knee prosthesis surface at a dose of 0.05 μg/mm²-10 μg/mm²of surface area coated. In one embodiment, talc is released from thesurface of a knee prosthesis such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, talc may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of talc (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent astalc is administered at half the above parameters, a compound half aspotent as talc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered from a knee prosthesis, or coated ontothe surface of a knee prosthesis, should not exceed 100 mg (range of 1μg to 100 mg). In one embodiment, the total amount of silk released fromthe prosthesis should be in the range of 10 μg to 50 mg. The dose perunit area of the device (i.e., the dosage of silk as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, silk should beapplied to a knee prosthesis surface at a dose of 0.05 μg/mm²-10 μg/mm²of surface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific medical devices can release silk atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the knee prosthesissuch that a minimum concentration of 0.01 nM to 1000 μM of silk isdelivered to the tissue. In one embodiment, silk is released from thesurface of a knee prosthesis such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, silk may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of silk (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent assilk is administered at half the above parameters, a compound half aspotent as silk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered from a knee prosthesis, or coatedonto the surface of a knee prosthesis, should not exceed 100 mg (rangeof 1 μg to 100 mg). In one embodiment, the total amount of chitosanreleased from the prosthesis should be in the range of 10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of chitosan as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.05μg-10 μg per mm² of surface area coated. In another embodiment, chitosanshould be applied to a knee prosthesis surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease chitosan at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from theknee prosthesis such that a minimum concentration of 0.01 nM to 1000 μMof chitosan is delivered to the tissue. In one embodiment, chitosan isreleased from the surface of a knee prosthesis (e.g., a bulking agent)such that fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, chitosan may be releasedin effective concentrations for a period ranging from 1 hour-30 days. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of chitosan (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as chitosan isadministered at half the above parameters, a compound half as potent aschitosan is administered at twice the above parameters, etc.).

Utilizing polylysine as a exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered from a knee prosthesis, or coatedonto the surface of a knee prosthesis, should not exceed 100 mg (rangeof 1 μg to 100 mg). In one embodiment, the total amount of polylysinereleased from the prosthesis should be in the range of 10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of polylysine asa function of the surface area of the portion of the device to whichdrug is applied and/or incorporated) should fall within the range of0.05 μg-10 μg per mm² of surface area coated. In another embodiment,polylysine should be applied to a knee prosthesis surface at a dose of0.05 μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease polylysine at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe knee prosthesis such that a minimum concentration of 0.01 nM to 1000μM of polylysine is delivered to the tissue. In one embodiment,polylysine is released from the surface of a knee prosthesis such thatfibrosis in the tissue is promoted for a period ranging from severalhours to several months. For example, polylysine may be released ineffective concentrations for a period ranging from 1 hour-30 days. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of polylysine (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as polylysine isadministered at half the above parameters, a compound half as potent aspolylysine is administered at twice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered from a knee prosthesis,or coated onto the surface of a knee prosthesis, should not exceed 100mg (range of 1 μg to 100 mg). In one embodiment, the total amount offibronectin released from the prosthesis should be in the range of 10 μgto 50 mg. The dose per unit area of the device (i.e., the dosage offibronectin as a function of the surface area of the portion of thedevice to which drug is applied and/or incorporated) should fall withinthe range of 0.05 μg-10 μg per mm² of surface area coated. In anotherembodiment, fibronectin should be applied to a knee prosthesis surfaceat a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificmedical devices can release fibronectin at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the knee prosthesis such that a minimumconcentration of 0.01 nM to 1000 μM of fibronectin is delivered to thetissue. In one embodiment, fibronectin is released from the surface of aknee prosthesis such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example,fibronectin may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives offibronectin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as fibronectin is administered at half theabove parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered from a knee prosthesis, or coatedonto the surface of a knee prosthesis, should not exceed 100 mg (rangeof 0.01 μg to 100 mg). In one embodiment, the total amount of bleomycinreleased from the prosthesis should be in the range of 0.10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of bleomycin as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.005μg-10 μg per mm² of surface area coated. In another embodiment,bleomycin should be applied to a knee prosthesis surface at a dose of0.005 μg/mm²-10 μg/mm² of surface area coated. As specific (polymericand non-polymeric) drug delivery vehicles and specific medical devicescan release bleomycin at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe knee prosthesis such that a minimum concentration of 0.001 nM to1000 μM of bleomycin is delivered to the tissue. In one embodiment,bleomycin is released from the surface of a knee prosthesis such thatfibrosis in the tissue is promoted for a period ranging from severalhours to several months. For example, bleomycin may be released ineffective concentrations for a period ranging from 1 hour-30 days. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of bleomycin (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as bleomycin isadministered at half the above parameters, a compound half as potent asbleomycin is administered at twice the above parameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered from a knee prosthesis, or coated ontothe surface of a knee prosthesis, should not exceed 100 mg (range of0.01 μg to 100 mg). In one embodiment, the total amount of CTGF releasedfrom the prosthesis should be in the range of 0.10 μg to 50 mg. The doseper unit area of the device (i.e., the dosage of CTGF as a function ofthe surface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.005 μg-10 μg permm² of surface area coated. In another embodiment, CTGF should beapplied to a knee prosthesis surface at a dose of 0.005 μg/mm²-10 μg/mm²of surface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific medical devices can release CTGF atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the knee prosthesissuch that a minimum concentration of 0.001 nM to 1000 μM of CTGF isdelivered to the tissue. In one embodiment, CTGF is released from thesurface of a knee prosthesis such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, CTGF may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of CTGF (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asCTGF is administered at half the above parameters, a compound half aspotent as CTGF is administered at twice the above parameters, etc.).

Optionally, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, and growth hormone) and/or a bone morphogenicprotein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or ananalogue or derivative thereof).

Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof) are to be used informulations at concentrations that range from 0.001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the bone morphogenic protein is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.001μg to 500 mg); preferred 1 μg to 250 mg. When used as a device coating,the dose is per unit area of 0.001 μg-1000 μg per mm²; with a preferreddose of 0.01 μg/mm²-200 μg/mm². Minimum concentration of 10⁻⁹-10⁻⁴ M ofbone morphogenic protein is to be maintained on the device surface.

Inflammatory cytokines are to be used in formulations at concentrationsthat range from 0.0001 μg/ml to approximately 20 mg/ml depending on thespecific clinical application, formulation type (e.g., gel, liquid,solid, semi-solid), formulation chemistry, duration of requiredapplication, type of medical device interface and formulation volume andor surface area coverage required. Preferably, the inflammatory cytokineis released in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see, e.g., Example 16). The proliferative agents areto be used in formulations at concentrations that range from 0.1 ng/mlto 25 mg/ml depending on the specific clinical application, formulationtype (e.g., gel, liquid, solid, semi-solid), formulation chemistry,duration of required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

(iii) Shoulder Implants

Shoulder joint reconstruction is typically indicated to alleviate painand restore lost function arising from medical conditions such asfractures, osteoarthritis, rheumatoid arthritis, avascular necrosis, andtumor growth (benign or malignant). Hemiarthroplasties (partial shoulderimplants), which involve implanting only the humeral components,typically are performed on patients suffering from shoulder fracturesand avascular necrosis. Total shoulder replacement (implanting of boththe humeral and glenoid components) is more common in patients sufferingfrom osteoarthritis and rheumatoid arthritis. Joint replacement inconjunction with excision of a tumor is fairly rare, occurring in lessthan one percent of patients who receive shoulder replacement surgeries.In a cancer patient, removal of bone may necessitate partial or totalreplacement of the joint.

Numerous shoulder prostheses have been described (see, e.g., U.S. Pat.Nos. 6,494,913; 6,193,758; 6,168,628; 6,102,953; 6,045,582; 5,961,555;5,593,448; 5,549,682; and 5,108,440). Shoulder implants suitable forcombining with one or more fibrosis-inducing agents according to thepresent invention, include numerous commercially available products.These include shoulder implants manufactured by DePuy Orthopaedics(e.g., GLOBAL TX Total Shoulder System, GLOBAL Shoulder Eccentric Head,GLOBAL Total Shoulder System), Biomet (e.g., Bio-Modular,Bi-Angular/Bi-Polar, Proximal Humeral Replacement, and IntegratedShoulder System), Stryker Howmedica Osteonics (e.g., SOLAR ShoulderBipolar Heads, Humeral Heads, Humeral Components, and GlenoidComponents), Sulzer (e.g., Anatomical Shoulder and Select Shoulder),Zimmer (Bigliani/Flatow Shoulder), and Smith & Nephew Orthopaedics(e.g., COFIELD 2 Total Shoulder System, NEER II Total Shoulder System,and Modular Shoulder System).

In one aspect, the present invention provides shoulder prostheses thatinclude a fibrosis-inducing agent or a composition that includes afibrosis-inducing agent to promote scarring and fixation of the deviceinto the surrounding bone. In one aspect, the shoulder prosthesis iscoated with a fibrosing agent or a composition that includes thefibrosing agent. In another aspect, the fibrosing agent may beincorporated into the glue or cement that holds the prosthesis in place.In another aspect, the shoulder prosthesis is covered (all or in part)with a silk mesh or lattice to encourage scarring and anchoring into thesurrounding bone. For example, a silk mesh or lattice can be coated ontoall or a portion of the surface of the implant stem to encouragescarring and anchoring into the surrounding bone.

Numerous polymeric and non-polymeric carrier systems described above canbe used in the practice of this embodiment. These compositions canfurther include one or more fibrosis-inducing agents to promote theformation of granulation tissue. Methods for incorporating fibrosingcompositions onto or into the orthopedic implants include: (a) directlyaffixing to the device a fibrosing composition (e.g., by either aspraying process or dipping process as described above, with or withouta carrier); (b) directly incorporating into the device a fibrosingcomposition (e.g., by either a spraying process or dipping process asdescribed above, with or without a carrier); (c) by coating the devicewith a substance such as a hydrogel which can in turn absorb thefibrosing composition; (d) by interweaving fibrosing composition coatedthread (or the polymer itself formed into a thread) into the devicestructure; (e) by inserting the device into a sleeve or mesh which iscomprised of or coated with a fibrosing composition; (f) constructingthe device itself or a portion of the device with a fibrosingcomposition; or (g) by covalently binding the fibrosing agent directlyto the device surface or to a linker (small molecule or polymer) that iscoated or attached to the device surface. For these devices, the coatingprocess can be performed in such a manner as to a) coat the surfaces ofthe device that is in contact with the bone, b) coat the surfaces of thedevice that are not in contact with the bone or c) coat all or parts ofboth the bone-contacting and non-bone contacting surface of the device.

In addition to coating the device with the fibrosing composition, thefibrosing agent can be mixed with the materials that are used to makethe device such that the fibrosing agent is incorporated into the finaldevice.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in shoulder prostheses include talc, silk,wool, chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well asanalogues and derivatives of the aforementioned.

As shoulder prostheses are made in a variety of configurations andsizes, the exact dose administered can vary with device size, surfacearea and design. However, certain principles can be applied in theapplication of this art. Drug dose can be calculated as a function ofdose per unit area (of the portion of the device being coated), totaldrug dose administered can be measured and appropriate surfaceconcentrations of active drug can be determined. Regardless of themethod of application of the drug to the shoulder prostheses, theexemplary fibrosing agents, used alone or in combination, should beadministered under the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered from a shoulder prosthesis, or coatedonto the surface of a shoulder prosthesis, should not exceed 100 mg(range of 1 μg to 100 mg). In one embodiment, the total amount of talcreleased from the prosthesis should be in the range of 10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of talc as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.05μg-10 μg per mm² of surface area coated. In another embodiment, talcshould be applied to a shoulder prosthesis surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. In one embodiment, talc isreleased from the surface of a shoulder prosthesis such that fibrosis inthe tissue is promoted for a period ranging from several hours toseveral months. For example, talc may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of talc (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as talc is administered at half the aboveparameters, a compound half as potent as talc is administered at twicethe above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered from a shoulder prosthesis, or coatedonto the surface of a shoulder prosthesis, should not exceed 100 mg(range of 1 μg to 100 mg). In one embodiment, the total amount of silkreleased from the prosthesis should be in the range of 10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of silk as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.05μg-10 μg per mm² of surface area coated. In another embodiment, silkshould be applied to a shoulder prosthesis surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease silk at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from theshoulder prosthesis such that a minimum concentration of 0.01 nM to 1000μM of silk is delivered to the tissue. In one embodiment, silk isreleased from the surface of a shoulder prosthesis such that fibrosis inthe tissue is promoted for a period ranging from several hours toseveral months. For example, silk may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of silk (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as silk is administered at half the aboveparameters, a compound half as potent as silk is administered at twicethe above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered from a shoulder prosthesis, orcoated onto the surface of a shoulder prosthesis, should not exceed 100mg (range of 1 μg to 100 mg). In one embodiment, the total amount ofchitosan released from the prosthesis should be in the range of 10 μg to50 mg. The dose per unit area of the device (i.e., the dosage ofchitosan as a function of the surface area of the portion of the deviceto which drug is applied and/or incorporated) should fall within therange of 0.05 μg-10 μg per mm² of surface area coated. In anotherembodiment, chitosan should be applied to a shoulder prosthesis surfaceat a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificmedical devices can release chitosan at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the shoulder prosthesis such that a minimumconcentration of 0.01 nM to 1000 μM of chitosan is delivered to thetissue. In one embodiment, chitosan is released from the surface of ashoulder prosthesis such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example,chitosan may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of chitosan(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as chitosan is administered at half the above parameters, acompound half as potent as chitosan is administered at twice the aboveparameters, etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered from a shoulder prosthesis, orcoated onto the surface of a shoulder prosthesis, should not exceed 100mg (range of 1 μg to 100 mg). In one embodiment, the total amount ofpolylysine released from the prosthesis should be in the range of 10 μgto 50 mg. The dose per unit area of the device (i.e., the dosage ofpolylysine as a function of the surface area of the portion of thedevice to which drug is applied and/or incorporated) should fall withinthe range of 0.05 μg-10 μg per mm² of surface area coated. In anotherembodiment, polylysine should be applied to a shoulder prosthesissurface at a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. Asspecific (polymeric and non-polymeric) drug delivery vehicles andspecific medical devices can release polylysine at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the shoulder prosthesis such that aminimum concentration of 0.01 nM to 1000 μM of polylysine is deliveredto the tissue. In one embodiment, polylysine is released from thesurface of a shoulder prosthesis such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, polylysine may be released in effective concentrations for aperiod ranging from 1 hour-30 days. It should be readily evident giventhe discussions provided herein that analogues and derivatives ofpolylysine (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as polylysine is administered at half the aboveparameters, a compound half as potent as polylysine is administered attwice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered from a shoulderprosthesis, or coated onto the surface of a shoulder prosthesis, shouldnot exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, thetotal amount of fibronectin released from the prosthesis should be inthe range of 10 μg to 50 mg. The dose per unit area of the device (i.e.,the dosage of fibronectin as a function of the surface area of theportion of the device to which drug is applied and/or incorporated)should fall within the range of 0.05 μg-10 μg per mm² of surface areacoated. In another embodiment, fibronectin should be applied to ashoulder prosthesis surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific medical devices can release fibronectinat differing rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the shoulderprosthesis such that a minimum concentration of 0.01 nM to 1000 μM offibronectin is delivered to the tissue. In one embodiment, fibronectinis released from the surface of a shoulder prosthesis such that fibrosisin the tissue is promoted for a period ranging from several hours toseveral months. For example, fibronectin may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of fibronectin (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as fibronectin is administered at halfthe above parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered from a shoulder prosthesis, orcoated onto the surface of a shoulder prosthesis, should not exceed 100mg (range of 0.01 μg to 100 mg). In one embodiment, the total amount ofbleomycin released from the prosthesis should be in the range of 0.10 μgto 50 mg. The dose per unit area of the device (i.e., the dosage ofbleomycin as a function of the surface area of the portion of the deviceto which drug is applied and/or incorporated) should fall within therange of 0.005 μg-10 μg per mm² of surface area coated. In anotherembodiment, bleomycin should be applied to a shoulder prosthesis surfaceat a dose of 0.005 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificmedical devices can release bleomycin at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the shoulder prosthesis such that a minimumconcentration of 0.001 nM to 1000 μM of bleomycin is delivered to thetissue. In one embodiment, bleomycin is released from the surface of ashoulder prosthesis such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example,bleomycin may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of bleomycin(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as bleomycin is administered at half the above parameters, acompound half as potent as bleomycin is administered at twice the aboveparameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered from a shoulder prosthesis, or coatedonto the surface of a shoulder prosthesis, should not exceed 100 mg(range of 0.01 μg to 100 mg). In one embodiment, the total amount ofCTGF released from the prosthesis should be in the range of 0.10 μg to50 mg. The dose per unit area of the device (i.e., the dosage of CTGF asa function of the surface area of the portion of the device to whichdrug is applied and/or incorporated) should fall within the range of0.005 μg-10 μg per mm² of surface area coated. In another embodiment,CTGF should be applied to a shoulder prosthesis surface at a dose of0.005 μg/mm²-10 μg/mm² of surface area coated. As specific (polymericand non-polymeric) drug delivery vehicles and specific medical devicescan release CTGF at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from theshoulder prosthesis such that a minimum concentration of 0.001 nM to1000 μM of CTGF is delivered to the tissue. In one embodiment, CTGF isreleased from the surface of a shoulder prosthesis such that fibrosis inthe tissue is promoted for a period ranging from several hours toseveral months. For example, CTGF may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of CTGF (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as CTGF is administered at half the aboveparameters, a compound half as potent as CTGF is administered at twicethe above parameters, etc.).

Optionally, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, and growth hormone) and/or a bone morphogenicprotein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or ananalogue or derivative thereof).

Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof) are to be used informulations at concentrations that range from 0.001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the bone morphogenic protein is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.001μg to 500 mg); preferred 1 μg to 250 mg. When used as a device coating,the dose is per unit area of 0.001 μg-1000 μg per mm²; with a preferreddose of 0.01 μg/mm²-200 μg/mm². Minimum concentration of 10⁻⁹-10⁻⁴ M ofbone morphogenic protein is to be maintained on the device surface.

Inflammatory cytokines are to be used in formulations at concentrationsthat range from 0.0001 μg/ml to approximately 20 mg/ml depending on thespecific clinical application, formulation type (e.g., gel, liquid,solid, semi-solid), formulation chemistry, duration of requiredapplication, type of medical device interface and formulation volume andor surface area coverage required. Preferably, the inflammatory cytokineis released in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see, e.g., Example 16). The proliferative agents areto be used in formulations at concentrations that range from 0.1 ng/mlto 25 mg/ml depending on the specific clinical application, formulationtype (e.g., gel, liquid, solid, semi-solid), formulation chemistry,duration of required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

(iv) Infiltration of Fibrosing-Inducing Agents into the TissueSurrounding an Artificial Joint

Alternatively, the tissue cavity into which the artificial joint isplaced (usually the bony cavity where the stem of the artificial jointis inserted) can be treated with a fibrosis-inducing agent prior to,during, or after the implantation of the prosthetic joint. This can beaccomplished in several ways including: (a) topical application of thefibrosing agent into the anatomical space where the artificial joint canbe placed (particularly useful for this embodiment is the use ofpolymeric carriers which release the fibrosing agent over a periodranging from several hours to several weeks—fluids, suspensions,emulsions, microemulsions, microspheres, pastes, gels,microparticulates, sprays, aerosols, solid implants and otherformulations which release a fibrosing agent can be delivered into theregion where the prosthetic joint can be inserted); (b) microparticulatesilk and/or silk strands (linear, branched, and/or coiled) for directeddelivery into the implantation site; (c) sprayable collagen-containingformulations such as COSTASIS or materials made from 4-armed thiol PEG(10K), a 4-armed NHS PEG (10K) and methylated collagen such as describedabove, either alone, or loaded with a fibrosis-inducing agent, appliedto the implantation site (or the implant/device surface); (d) sprayablePEG-containing formulations such as COSEAL, FOCALSEAL, SPRAYGEL orDURASEAL, either alone, or loaded with a fibrosis-inducing agent,applied to the implantation site (or the implant/device surface); (e)fibrinogen-containing formulations such as FLOSEAL or TISSEAL, eitheralone, or loaded with a fibrosis-inducing agent, applied to theimplantation site (or the implant/device surface); (f) hyaluronicacid-containing formulations such as RESTYLANE, HYLAFORM, PERLANE,SYNVISC, SEPRAFILM, SEPRACOAT loaded with a fibrosis-inducing agentapplied to the implantation site (or the implant/device surface); (g)polymeric gels for surgical implantation such as REPEL or FLOWGEL loadedwith a fibrosis-inducing agent applied to the implantation site (or theimplant/device surface); (h) orthopedic cements used to hold prosthesesand tissues in place loaded with a fibrosis-inducing agent applied tothe implantation site (or the implant/device surface), such asOSTEOBOND, LVC, SIMPLEX P, PALACOS, and ENDURANCE; (i) surgicaladhesives containing cyanoacrylates such as DERMABOND, INDERMIL,GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYLBLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or as described above,either alone, or loaded with a fibrosis-inducing agent, applied to theimplantation site (or the implant/device surface); (j) implantscontaining hydroxyapatite (or synthetic bone material such as calciumsulfate, VITOSS and CORTOSS) loaded with a fibrosis-inducing agentapplied to the implantation site (or the implant/device surface); (k)other biocompatible tissue fillers loaded with a fibrosis-inducingagent, such as those made by BioCure, 3M Company and Neomend, loadedwith a fibrosis-inducing agent applied to the implantation site (or theimplant/device surface); (l) polysaccharide gels such as the ADCONseries of gels; (m) films, sponges or meshes such as INTERCEED, VICRYLmesh, and GELFOAM either alone, or loaded with a fibrosis-inducingagent, bone morphogenic protein, and/or growth factor, injected into oraround the joint; and/or (n) a hydrogel that is formed from anamino-functionalized polyethylene glycol (e.g., 4-armed tetra-amino PEG[10k]) and a 4-armed NHS functionalized PEG (e.g., pentaerythritolpoly(ethylene glycol)ether tetra-succinimidyl glutarate [10K]). Thishydrogel may further contain collagen, methylated collagen and/orgelatin. This hydrogel can further comprise the fibrosis-inducing agentsdescribed above (e.g., silk powder or silk threads).(m) films, spongesor meshes such as INTERCEED, VICRYL mesh, and GELFOAM loaded with afibrosis-inducing agent applied to the implantation site (or theimplant/device surface).

It should be apparent to one of skill in the art that potentially anyfibrosis-inducing agents described above may be utilized alone, or incombination, in the practice of this embodiment. Exemplary fibrosingagents for infiltration into the tissues surrounding a joint prosthesisinclude talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin,and CTGF, as well as analogues and derivatives of the aforementioned.

As joint prostheses are made in a variety of configurations and sizes,the exact dose administered into the tissue surrounding the implant canvary with device size, surface area and design. However, certainprinciples can be applied in the application of this art. Drug dose canbe calculated as a function of dose per unit area (of the implantedportion of the device), total drug dose administered can be measured andappropriate surface concentrations of active drug can be determined.Regardless of the method of application of the drug, the exemplaryfibrosing agents, used alone or in combination, should be administeredunder the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymeric carrier or applied without a polymericcarrier, the total dose of talc delivered should not exceed 100 mg(range of 1 μg to 100 mg). In one embodiment, the total amount of talcreleased from around the prosthesis should be in the range of 10 μg to50 mg. The dose per unit area of the device (i.e., the dosage of talc asa function of the surface area of the implanted portion of the device)should fall within the range of 0.05 μg-10 μg per mm². In oneembodiment, talc is released such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, talc may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of talc (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent astalc is administered at half the above parameters, a compound half aspotent as talc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymeric carrier or applied without a polymericcarrier, the total dose of silk delivered into the tissue surrounding aprosthesis should not exceed 100 mg (range of 1 μg to 100 mg). In oneembodiment, the total amount of silk released around the prosthesisshould be in the range of 10 μg to 50 mg. The dose per unit area of thedevice (i.e., the dosage of silk as a function of the surface area ofthe portion of the device which is implanted) should fall within therange of 0.05 μg-10 μg per mm². As specific (polymeric andnon-polymeric) drug delivery vehicles can release silk at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug such that a minimum concentration of0.01 nM to 1000 μM of silk is delivered to the tissue. In oneembodiment, silk is released into the tissue surrounding a prosthesissuch that fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, silk may be released ineffective concentrations for a period ranging from 1 hour-30 days. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of silk (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as silk is administered at half theabove parameters, a compound half as potent as silk is administered attwice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymeric carrier or applied without a polymericcarrier, the total dose of chitosan delivered into the tissuesurrounding a prosthesis should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of chitosan released around theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of chitosan as a function of thesurface area of the portion of the device which is implanted) shouldfall within the range of 0.05 μg-10 μg per mm². As specific (polymericand non-polymeric) drug delivery vehicles can release chitosan atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug such that a minimumconcentration of 0.01 nM to 1000 μM of chitosan is delivered to thetissue. In one embodiment, chitosan is released into the tissuesurrounding a prosthesis such that fibrosis in the tissue is promotedfor a period ranging from several hours to several months. For example,chitosan may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of chitosan(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as chitosan is administered at half the above parameters, acompound half as potent as chitosan is administered at twice the aboveparameters, etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, whether itis applied using a polymeric carrier or applied without a polymericcarrier, the total dose of polylysine delivered into the tissuesurrounding a prosthesis should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of polylysine released shouldbe in the range of 10 μg to 50 mg. The dose per unit area of the device(i.e., the dosage of polylysine as a function of the surface area of theimplanted portion of the device) should fall within the range of 0.05μg-10 μg per mm². As specific (polymeric and non-polymeric) drugdelivery vehicles can release polylysine at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug such that a minimum concentration of 0.01 nM to 1000 μMof polylysine is delivered to the tissue. In one embodiment, polylysineis released into the region surrounding a prosthesis such that fibrosisin the tissue is promoted for a period ranging from several hours toseveral months. For example, polylysine may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of polylysine (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as polylysine is administered at halfthe above parameters, a compound half as potent as polylysine isadministered at twice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymeric carrier or applied without a polymericcarrier, the total dose of fibronectin delivered into the tissuesurrounding a prosthesis should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of fibronectin released shouldbe in the range of 10 μg to 50 mg. The dose per unit area of the device(i.e., the dosage of fibronectin as a function of the surface area ofthe portion of the device which is implanted) should fall within therange of 0.05 μg-10 μg per mm². As specific (polymeric andnon-polymeric) drug delivery vehicles can release fibronectin atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug such that a minimumconcentration of 0.01 nM to 1000 μM of fibronectin is delivered to thetissue surrounding the prosthesis. In one embodiment, fibronectin isreleased adjacent to the artificial joint such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, fibronectin may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of fibronectin (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as fibronectin is administered at halfthe above parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymeric carrier or applied without a polymericcarrier, the total dose of bleomycin delivered into the tissuesurrounding a prosthesis should not exceed 100 mg (range of 0.01 μg to100 mg). In one embodiment, the total amount of bleomycin releasedshould be in the range of 0.10 μg to 50 mg. The dose per unit area ofthe device (i.e., the dosage of bleomycin as a function of the surfacearea of the portion of the device which is implanted) should fall withinthe range of 0.005 μg-10 μg per mm². As specific (polymeric andnon-polymeric) drug delivery vehicles can release bleomycin at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug such that a minimum concentration of0.001 nM to 1000 μM of bleomycin is delivered to the tissue surroundingthe joint prosthesis. In one embodiment, bleomycin is released aroundthe prosthesis such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, bleomycin maybe released in effective concentrations for a period ranging from 1hour-30 days. It should be readily evident given the discussionsprovided herein that analogues and derivatives of bleomycin (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asbleomycin is administered at half the above parameters, a compound halfas potent as bleomycin is administered at twice the above parameters,etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymeric carrier or applied without a polymericcarrier, the total dose of CTGF delivered into the tissue surrounding aprosthesis should not exceed 100 mg (range of 0.01 μg to 100 mg). In oneembodiment, the total amount of CTGF released should be in the range of0.10 μg to 50 mg. The dose per unit area of the device (i.e., the dosageof CTGF as a function of the surface area of the portion of the devicewhich is implanted) should fall within the range of 0.005 μg-10 μg permm². As specific (polymeric and non-polymeric) drug delivery vehiclescan release CTGF at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug such that aminimum concentration of 0.001 nM to 1000 μM of CTGF is delivered to thetissue surrounding the artificial joint. In one embodiment, CTGF isreleased such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, CTGF may bereleased in effective concentrations for a period ranging from 1 hour-30days. It should be readily evident given the discussions provided hereinthat analogues and derivatives of CTGF (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as CTGF isadministered at half the above parameters, a compound half as potent asCTGF is administered at twice the above parameters, etc.).

Optionally, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, and growth hormone) and/or a bone morphogenicprotein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or ananalogue or derivative thereof).

Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof) are to be used informulations at concentrations that range from 0.001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the bone morphogenic protein is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.001μg to 500 mg); preferred 1 μg to 250 mg. When used as a device coating,the dose is per unit area of 0.001 μg-1000 μg per mm²; with a preferreddose of 0.01 μg/mm²-200 μg/mm². Minimum concentration of 10⁻⁹-10⁴ M ofbone morphogenic protein is to be maintained on the device surface.

Inflammatory cytokines are to be used in formulations at concentrationsthat range from 0.0001 μg/ml to approximately 20 mg/ml depending on thespecific clinical application, formulation type (e.g., gel, liquid,solid, semi-solid), formulation chemistry, duration of requiredapplication, type of medical device interface and formulation volume andor surface area coverage required. Preferably, the inflammatory cytokineis released in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see, e.g., Example 16). The proliferative agents areto be used in formulations at concentrations that range from 0.1 ng/mlto 25 mg/ml depending on the specific clinical application, formulationtype (e.g., gel, liquid, solid, semi-solid), formulation chemistry,duration of required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

3. Dental Devices

In one aspect, the present invention provides dental devices andimplants that include a fibrosis or adhesion-inducing agent to assist inthe incorporation of the implant into the surrounding tissue. A varietyof devices is used in dental applications. Representative examplesinclude dental implants and guided bone regeneration devices.

In one aspect, a dental implant of specific importance is a smalltitanium fixture that serves as a replacement for the root portion of amissing natural tooth. The dental implant is placed in the bone of theupper or lower jaw and functions as an anchor for the replacement tooth.They may be used to support the replacement of a single missing tooth ora complete functional set for individuals who have lost many or all oftheir teeth. Dental implants can be implanted in the bone (endosteal) oron the bone (subperiosteal). Endosteal implants are the most commonlyused type of implant. There are various types of endosteal implants,which may include screws, cylinders or blades surgically placed into thejawbone. Each implant holds one or more prosthetic teeth. This type ofimplant is generally used as an alternative for patients with bridges orremovable dentures. Subperiosteal implants are placed on top of the jawwith the metal framework's posts protruding through the gum to hold theprosthesis. These types of implants are used for patients who are unableto wear conventional dentures and who have minimal bone height.

A variety of dental implants suitable for combination with afibrosis-inducing agent have been described (see, e.g., U.S. Pat. Nos.6,627,321; 6,582,228; 6,572,373; 6,527,553; and 6,506,051).

In one aspect, the fibrosing agent may be incorporated into the glue orcement that holds the device in place. In another aspect, the dentaldevice is covered (all or in part) with a silk mesh or lattice toencourage scarring and anchoring into the surrounding bone. For example,a silk mesh or lattice can be coated onto all or a portion of thesurface of the implant stem to encourage scarring and anchoring into thesurrounding bone.

In another aspect, the device used to deliver a fibrosis-inducing agentmay be a guided tissue regeneration (GTR) device, such as a GTRmembrane. A GTR membrane is a resorbable or non-resorbable membrane madeof biologically or non-biologically derived material. GTR membranes maybe used in conjunction with a dental implant or to treat bone loss. GTRmembranes may be made from a variety of materials, including, e.g.,collagen (e.g., porcine collagen, types I and II), PTFE, polylacticacid, lactide and glycolide polymers, and ePTFE). GTR membranes arecommercially available from W.L. Gore & Associates (Newark, Del.) (e.g.,GORE-TEX and GORE-RESOLUT regenerative material), Guidor, AtrixLaboratories, Inc. (Fort Collins, Colo.), Geistlich Biomaterials, Inc.(e.g., BIO-GIDE), LifeCore Biomedical, Inc. (Chaska, Minn.), EthiconInc. (e.g., VICRYL), THM Biomedical now known as Kensey Nash Corporation(Exton, Pa.), and Suzler Calcitek, Inc. (Carlsbad, Calif.).

In another aspect, the dental device suitable for combining with afibrosis-inducing agent is used for guided bone regeneration (GBR) toaugment insufficient bone tissue and guide regrowth. GBR devicesinclude, e.g., resorbable bone substitutes for filling bony defects.Such devices may consist of biomaterials (e.g., demineralized bone andbovine-derived materials) and synthetic materials, such as crystallinehydroxyapatite and calcium sulfate. A variety of dental bone substitutesare commercially available, including the following products:OSTEOGRAF/N, OSTEOGRAF/LD, OSTEOGRAF/D, AND PERMARIDGE (all fromCeramad), bioactive glass, such as PERIOGLAS (U.S. Biomaterials),OSTEOGEN (Impladent, Inc.), VITOSS and CORTOSS.

In another aspect, the present invention provides dental implantscontaining a fibrosis-inducing agent for use in the treatment of commonperiodontal conditions. Briefly, periodontal disease is an inflammatorydisease of the supporting structures of the teeth, including theligaments, cementum, periosteum, alveolar bone and adjacent gingivawhich anchor the teeth in place. The condition begins with bleeding ofthe gums, but can progress to loosening of the teeth, receding gums,abscesses in pockets between the gums and the teeth, and necrotizingulcerative gingivitis. In advanced stages, procedures such asgingivectomy, gingivoplasty, and correction of the bony architecture ofthe teeth may be required for treatment of the condition. Traditionaltreatment involves open-flap debridement of the periodontal pocket withremoval of diseased cementum, periodontal ligament and alveolar bonethat have been destroyed by periodontal infection. Unfortunately,epithelial tissue can occasionally migrate into the surgically createddefect impairing proper healing of the cementum, ligament and bone.

Dental implants have been developed in an attempt to control the healingprocess and optimize tissue regeneration. Commonly used implants includepermanent implants, such as e-PTFE membranes (e.g., GORE-TEX from W.L.Gore). Commonly used implants include, e.g., BIOMEND, available fromSulzer Medica, Inc. (Houston, Tex.), which is a collagen membranecomposed of compressed Type I collagen matrix derived from bovineAchilles tendon. The collagen membrane (supplied as sheets, e.g., 15mm×20 mm; 20 mm×30 mm; and 30 mm×40 mm) is cut to the appropriate sizeand shape, hydrated and placed as a barrier between the overlyinggingival tissue and the debrided periodontal defect; the barrier can besutured in place, but this is not always required. The membrane isplaced snugly against the tooth root and draped over the surroundingalveolar bone (extending at least 3 mm beyond the defect margins) toeffectively maintain the regenerative space. Primary closure withmucoperiosteal flaps over the collagen membrane is important as exposureof the membrane to the oral cavity can result in premature degradation.The barrier prevents faster growing epithelial tissue from entering theregion and allows the slower growing periodontal ligament and bone cellsto repopulate the area and effect appropriate healing. The collagenmembrane is bioresorbable, is retained for 6 to 7 weeks, and is fullyabsorbed by host enzymes (e.g., collagenase) within 8 weeks.

However, limited durability of the collagen implant can become aclinical problem if it completely absorbs prior to the completion ofhealing—this is particularly relevant with large tissue defects. In anattempt to address this problem, manufacturers have attempted to producea collagen implant with improved durability through increased collagencrosslinking (often through exposure of the collagen to aldehydes).Utilizing this process, products such as BIOMEND EXTEND (Sulzer Medica,Inc.) can function as a barrier for longer periods of time, such thatthe collagen is not absorbed into the surrounding tissue forapproximately 18 weeks. Another collagen dental implant product, OSSIX(Colbar R&D Ltd., Israel), uses a metabolite to crosslink collagen andprolong the structural integrity of the matrix for periods of up to 6months.

In addition to the commercially available collagen-based products forthe management of periodontal disease described above, other types ofcollagen-based implants may be used in the practice of the invention.Representative examples of such implants include those that are used invariety of dental procedures including: COLLATAPE (Sulzer Medica, Inc.),which is a collagen-based implant used in the repair of minor oralwounds, closure of grafted sites and repair of Schneiderian Membranes;COLLACOTE (Sulzer Medica, Inc.), a collagen-based wound dressing usedfor palatal donor sites and in mucosal flaps; and COLLAPLUG (SulzerMedica, Inc.), a solid collagen-based implant used in the repair oflarger tissue defects such extraction sites or biopsy sites.

In one aspect, the present invention provides dental devices thatinclude a fibrosis-inducing agent or a composition that includes afibrosis-inducing agent to promote fibrosis in the periodontal pocket.In one aspect, the dental device or material used to fill or maintainthe periodontal pocket is coated with, composed of, or contains afibrosing agent or a composition that includes a fibrosing agent.

Numerous polymeric and non-polymeric carrier systems described above canbe used in the practice of this embodiment. These compositions canfurther include one or more fibrosis-inducing agents to promote theformation of fibrous tissue around the dental implant. Methods forincorporating fibrosing compositions onto or into the dental implant(such as endosteal or perioosteal titanium implants) include: (a)directly affixing to the dental hardware a fibrosing composition (e.g.,by either a spraying process or dipping process as described above, withor without a carrier); (b) directly incorporating into the dentalhardware a fibrosing composition (e.g., by either a spraying process ordipping process as described above, with or without a carrier); (c) bycoating the dental hardware with a substance such as a hydrogel whichcan in turn absorb the fibrosing composition; (d) by interweaving athread coated with a fibrosis-inducing composition (or the afibrosis-inducing polymer itself formed into a thread) into the devicestructure; (e) by inserting the device into a sleeve or mesh which iscomprised of, or coated with, a fibrosing composition; (f) constructingthe device itself, or a portion of the device, with a compositioncontaining a fibrosing agent; or (g) by covalently binding the fibrosingagent directly to the device surface or to a linker (small molecule orpolymer) that is coated or attached to the device surface. For dentalhardware devices, the coating process can be performed in such a manneras to (a) coat the surfaces of the device that is in contact with thebone, (b) coat the surfaces of the device that are not in contact withthe bone or (c) coat all or parts of both the bone-contacting andnon-bone contacting surface of the device. In addition to coating thedevice with the fibrosing composition, the fibrosing agent can be mixedwith the materials that are used to make the device such that thefibrosing agent is incorporated into the final device.

For the management of periodontal disease, polymeric gels, pastes,injectables, solutions, microparticles and solid implants placed intothe periodontal pocket are a preferred form of locally delivering afibrosis-inducing agent. All involve the deployment of a biomaterialcontaining a fibrosis-inducing agent into the surgically-createdperiodontal pocket (as described above). The practice of this embodimentcan be performed in several ways including: (a) topical application ofthe fibrosing agent onto the periodontal pocket (particularly useful forthis embodiment is the use of polymeric carriers which release thefibrosing agent over a period ranging from several hours to severalweeks—fluids, suspensions, emulsions, microemulsions, microspheres,pastes, gels, microparticulates, sprays, aerosols, solid implants andother formulations which release a fibrosing agent and can be deliveredinto the region via specialized delivery catheters or otherapplicators); (b) placement of microparticulate silk and/or silk strands(linear, branched, and/or coiled) into the periodontal pocket; (c)sprayable collagen-containing formulations such as COSTASIS or materialsmade from 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and methylatedcollagen such as described above, either alone, or loaded with afibrosis-inducing agent, applied into periodontal pocket; (d) sprayablePEG-containing formulations such as COSEAL, FOCALSEAL, SPRAYGEL orDURASEAL, either alone, or loaded with a fibrosis-inducing agent,applied to the periodontal pocket; (e) fibrinogen-containingformulations such as FLOSEAL or TISSEAL, either alone, or loaded with afibrosis-inducing agent, applied to the periodontal pocket; (f)hyaluronic acid-containing formulations such as RESTYLANE, HYLAFORM,PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT loaded with a fibrosis-inducingagent applied to the periodontal pocket; (g) polymeric gels for surgicalimplantation such as REPEL or FLOWGEL loaded with a fibrosis-inducingagent applied to the periodontal pocket; (h) orthopedic “cements” suchas OSTEOBOND, LVC, SIMPLEX P, PALACOS, ENDURANCE, and CORTOSS loadedwith a fibrosis-inducing agent applied to the periodontal pocket; (i)surgical adhesives containing cyanoacrylates such as DERMABOND,INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II,HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or asdescribed above loaded with a fibrosis-inducing agent, applied to theperiodontal pocket; (j) surgical implants containing hydroxyapatite,calcium sulfate, or VITOSS loaded with a fibrosis-inducing agent appliedto the periodontal pocket; (k) other biocompatible tissue fillers, suchas those made by BioCure, 3M Company and Neomend, loaded with afibrosis-inducing agent, applied to the periodontal pocket; (l)polysaccharide gels such as the ADCON series of gels loaded with afibrosis-inducing agent applied to the periodontal pocket; (m) films,sponges or meshes such as INTERCEED, VICRYL mesh, and GELFOAM loadedwith a fibrosis-inducing agent applied to the periodontal pocket; and/or(n) a hydrogel that is formed from an amino-functionalized polyethyleneglycol (e.g., 4-armed tetra-amino PEG [10k]) and a 4-armed NHSfunctionalized PEG (e.g., pentaerythritol poly(ethylene glycol)ethertetra-succinimidyl glutarate [10K]). This hydrogel may further containcollagen, methylated collagen and/or gelatin. This hydrogel can furthercomprise the fibrosis-inducing agents described above (e.g., silk powderor silk threads).

In many of the embodiments described above it may also be useful to adda radio-opaque material (such as tantalum, barium, other metal, orcontrast material) such that the injected material can be visualizedradiographically or by MRI. The contrast agent may be a water soluble orwater insoluble radio-opaque material.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in dental prostheses include talc, silk, wool,chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well asanalogues and derivatives of the aforementioned.

Optionally, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, and growth hormone) or a bone morphogenic protein(BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogueor derivative thereof).

As dental prostheses are made in a variety of configurations and sizes,the exact dose administered can vary with device size, surface area anddesign. However, certain principles can be applied in the application ofthis art. Drug dose can be calculated as a function of dose per unitarea (of the portion of the device being coated), total drug doseadministered can be measured and appropriate surface concentrations ofactive drug can be determined. Regardless of the method of applicationof the drug to the dental prostheses or periodontal implant, theexemplary fibrosing agents, used alone or in combination, should beadministered under the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered from a dental prosthesis, or coatedonto the surface of a dental prosthesis, should not exceed 100 mg (rangeof 1 μg to 100 mg). In one embodiment, the total amount of talc releasedfrom the prosthesis should be in the range of 10 μg to 50 mg. The doseper unit area of the device (i.e., the dosage of talc as a function ofthe surface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, talc should beapplied to a dental prosthesis surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. In one embodiment, talc is released fromthe surface of a dental prosthesis such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, talc may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of talc (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent astalc is administered at half the above parameters, a compound half aspotent as talc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered from a dental prosthesis, or coatedonto the surface of a dental prosthesis, should not exceed 100 mg (rangeof 1 μg to 100 mg). In one embodiment, the total amount of silk releasedfrom the prosthesis should be in the range of 10 μg to 50 mg. The doseper unit area of the device (i.e., the dosage of silk as a function ofthe surface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μ-10 μg permm² of surface area coated. In another embodiment, silk should beapplied to a dental prosthesis surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can release silk atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the dental prosthesissuch that a minimum concentration of 0.01 nM to 1000 μM of silk isdelivered to the tissue. In one embodiment, silk is released from thesurface of a dental prosthesis such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, silk may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of silk (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent assilk is administered at half the above parameters, a compound half aspotent as silk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered from a dental prosthesis, or coatedonto the surface of a dental prosthesis, should not exceed 100 mg (rangeof 1 μg to 100 mg). In one embodiment, the total amount of chitosanreleased from the prosthesis should be in the range of 10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of chitosan as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.05μg-10 μg per mm² of surface area coated. In another embodiment, chitosanshould be applied to a dental prosthesis surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease chitosan at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from thedental prosthesis such that a minimum concentration of 0.01 nM to 1000μM of chitosan is delivered to the tissue. In one embodiment, chitosanis released from the surface of a dental prosthesis such that fibrosisin the tissue is promoted for a period ranging from several hours toseveral months. For example, chitosan may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of chitosan (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as chitosan is administered at halfthe above parameters, a compound half as potent as chitosan isadministered at twice the above parameters, etc.).

Utilizing polylysine as a exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered from a dental prosthesis, orcoated onto the surface of a dental prosthesis, should not exceed 100 mg(range of 1 μg to 100 mg). In one embodiment, the total amount ofpolylysine released from the prosthesis should be in the range of 10 μgto 50 mg. The dose per unit area of the device (i.e., the dosage ofpolylysine as a function of the surface area of the portion of thedevice to which drug is applied and/or incorporated) should fall withinthe range of 0.05 μg-10 μg per mm² of surface area coated. In anotherembodiment, polylysine should be applied to a dental prosthesis surfaceat a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificmedical devices can release polylysine at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the dental prosthesis such that a minimumconcentration of 0.01 nM to 1000 μM of polylysine is delivered to thetissue. In one embodiment, polylysine is released from the surface of adental prosthesis such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example,polylysine may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of polylysine(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as polylysine is administered at half the above parameters, acompound half as potent as polylysine is administered at twice the aboveparameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered from a dentalprosthesis, or coated onto the surface of a dental prosthesis, shouldnot exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, thetotal amount of fibronectin released from the prosthesis should be inthe range of 10 μg to 50 mg. The dose per unit area of the device (i.e.,the dosage of fibronectin as a function of the surface area of theportion of the device to which drug is applied and/or incorporated)should fall within the range of 0.05 μg-10 μg per mm² of surface areacoated. In another embodiment, talc should be applied to a dentalprosthesis surface at a dose of 0.05 μg/mm²-10 μg/mm² of surface areacoated. As specific (polymeric and non-polymeric) drug delivery vehiclesand specific medical devices can release fibronectin at differing rates,the above dosing parameters should be utilized in combination with therelease rate of the drug from the dental prosthesis such that a minimumconcentration of 0.01 nM to 1000 μM of fibronectin is delivered to thetissue. In one embodiment, fibronectin is released from the surface of adental prosthesis such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example,fibronectin may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives offibronectin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as fibronectin is administered at half theabove parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as a exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered from a dental prosthesis, orcoated onto the surface of a dental prosthesis, should not exceed 100 mg(range of 0.01 μg to 100 mg). In one embodiment, the total amount ofbleomycin released from the prosthesis should be in the range of 0.10 μgto 50 mg. The dose per unit area of the device (i.e., the dosage ofbleomycin as a function of the surface area of the portion of the deviceto which drug is applied and/or incorporated) should fall within therange of 0.005 μg-10 μg per mm² of surface area coated. In anotherembodiment, bleomycin should be applied to a dental prosthesis surfaceat a dose of 0.005 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificmedical devices can release bleomycin at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the dental prosthesis such that a minimumconcentration of 0.001 nM to 1000 μM of bleomycin is delivered to thetissue. In one embodiment, bleomycin is released from the surface of adental prosthesis such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example,bleomycin may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of bleomycin(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as bleomycin is administered at half the above parameters, acompound half as potent as bleomycin is administered at twice the aboveparameters, etc.).

Utilizing CTGF as a exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered from a dental prosthesis, or coatedonto the surface of a dental prosthesis, should not exceed 100 mg (rangeof 0.01 μg to 100 mg). In one embodiment, the total amount of CTGFreleased from the prosthesis should be in the range of 0.10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of CTGF as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.005μg-10 μg per mm² of surface area coated. In another embodiment, CTGFshould be applied to a dental prosthesis surface at a dose of 0.005μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease CTGF at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from thedental prosthesis such that a minimum concentration of 0.001 nM to 1000μM of CTGF is delivered to the tissue. In one embodiment, CTGF isreleased from the surface of a dental prosthesis such that fibrosis inthe tissue is promoted for a period ranging from several hours toseveral months. For example, CTGF may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of CTGF (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as CTGF is administered at half the aboveparameters, a compound half as potent as CTGF is administered at twicethe above parameters, etc.).

Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof), if present, are to be usedin formulations at concentrations that range from 0.001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the bone morphogenic protein is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.001μg to 500 mg); preferred 1 μg to 250 mg. When used as a device coating,the dose is per unit area of 0.001 μg-1000 μg per mm²; with a preferreddose of 0.01 μg/mm²-200 μg/mm². Minimum concentration of 10⁻⁹-10⁻⁴ M ofbone morphogenic protein is to be maintained on the device surface.

Inflammatory cytokines, if present, are to be used in formulations atconcentrations that range from 0.0001 μg/ml to approximately 20 mg/mldepending on the specific clinical application, formulation type (e.g.,gel, liquid, solid, semi-solid), formulation chemistry, duration ofrequired application, type of medical device interface and formulationvolume and or surface area coverage required. Preferably, theinflammatory cytokine is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 100 mg);preferred 0.001 μg to 50 mg. When used as a device coating, the dose isper unit area of 0.0001 μg-500 μg per mm²; with a preferred dose of0.001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹⁰-10⁻⁴ g/ml ofinflammatory cytokine is to be maintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D_(3,) diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see, e.g., Example 16). The proliferative agents areto be used in formulations at concentrations that range from 0.0.1 ng/mlto 25 mg/ml depending on the specific clinical application, formulationtype (e.g., gel, liquid, solid, semi-solid), formulation chemistry,duration of required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

4. Orthopedic Implants

In one aspect, the present invention provides orthopedic implants thatinclude a fibrosis-inducing agent or a composition that includes afibrosis-inducing agent to promote scarring and fixation of the deviceinto the surrounding bone or tissue.

(i) Orthopedic Hardware Coated with a Fibrosis-Inducing Agent

In one aspect, the orthopedic implant is an orthopedic “hardware” devicethat has been coated with a fibrosing agent or a fibrosing agentcontaining composition. Representative examples of orthopedic hardwaredevices include internal and external fixation devices, fixation screws(degradable or non-degradable), interferential screws (degradable andnon-degradable), trochanteric screws, plates, wires (e.g., K-wires),pins, and nails used in fracture repairs, reconstructive procedures, andjoint fusion procedures (e.g., ankle fusions, cervical and lumbar spinalfusions). Compositions also are provided for coating devices used infusion procedures and superior repair of fractures. Orthopedic implantssuch as, for example, fixation screws, pins, plates, nails, wires andplates coated with a fibrosing agent, coated with a compositioncontaining a fibrosing agent, or composed of a polymer that releases afibrosing agent (particularly for polymeric, biodegradable orthopedichardware) are used to encourage better anchorage of the implant into thesurrounding bone. Alternatively, or in addition, the fibrosing agent maybe incorporated into the glue or cement that holds the implant in place.In another aspect, the orthopedic hardware is covered (all or in part)with a silk mesh or lattice to encourage scarring and anchoring into thesurrounding bone. For example, a silk mesh or lattice can be coated ontoall or a portion of the surface of the implant stem to encouragescarring and anchoring into the surrounding bone.

In another aspect, the orthopedic implant is a collagen implant for useas a substitute for autogenous or allogenous bone grafts. A variety ofcollagen implants have been developed for use in orthopedic surgery as asubstitute for autogenous or allogenous bone grafts. Collagen is theprinciple organic component of bone and can be combined with mineralformulations, autogenous bone marrow, bone graft, and/or growth factors(such as BMPs) for use as a bone substitute or a skeletal repairproduct. Typical applications include, but are not restricted to, totaljoint replacement surgery (e.g., artificial hips, knees, etc.), spinalfusion surgery, long bone fractures, repair of traumatic bone defects,voids, or gaps, to augment an autograft, and as a bone filler at bonegraft harvesting sites. Examples of commercially availablecollagen-based bone grafts include COLLAGRAFT Paste and COLLAGRAFTStrips made by Angiotech Pharmaceuticals, Inc. COLLAGRAFT is acombination of highly purified Type I bovine dermal fibrillar collagenand a mixture of 65% hydroxyapatite and 35% tricalcium phosphate. Thismaterial closely resembles human bone and is resorbed and replaced withbone during the healing process. Representative examples of bone graftsare described in U.S. Pat. Nos. 6,083,522 and 6,280,474 and in PCTPublication No. WO 98/52498.

Numerous polymeric and non-polymeric carrier systems described above canbe used in the practice of this embodiment. These compositions canfurther include one or more fibrosis-inducing agents to promote theformation of granulation tissue (described further in section (iii)below). Methods for incorporating fibrosing compositions onto or intothe orthopedic implants include: (a) directly affixing to the device afibrosing composition (e.g., by either a spraying process or dippingprocess as described above, with or without a carrier); (b) directlyincorporating into the device a fibrosing composition (e.g., by either aspraying process or dipping process as described above, with or withouta carrier); (c) by coating the device with a substance such as ahydrogel which can in turn absorb the fibrosing composition; (d) byinterweaving into the device a thread coated with a fibrosingcomposition (or a polymeric version of the fibrosing agent is itselfformed into a thread); (e) by inserting the device into a sleeve or meshwhich is comprised of, or coated with, a fibrosing composition; (f)constructing the device itself or a portion of the device with afibrosing composition (particularly effective for biodegradableorthopedic hardware and collagen implants); or (g) by covalently bindingthe fibrosing agent directly to the device surface or to a linker (smallmolecule or polymer) that is coated or attached to the device surface.For these devices, the coating process can be performed in such a manneras to (a) coat the surfaces of the device that is in contact with thebone; (b) coat the surfaces of the device that are not in contact withbone, or (c) coat all or parts of both the bone-contacting and non-bonecontacting surface of the device.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agent may be utilized alone, or incombination, in the practice of this embodiment as described above.Exemplary fibrosing agents for use in the coating of orthopedic hardwareinclude talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin,and/or CTGF as well as analogues and derivatives of the aforementioned.The correct administration and dosage is the same as that describedpreviously in section 2(i), 2(ii) and 2(iii) for artificial hips, kneesand shoulder prostheses.

(ii) Minimally-Invasive Joint Fusion

In another aspect, the present invention provides injectablecompositions to promote scarring and fixation (immobilization) of ajoint without the need for open surgery. In some clinical situations itis desirable to immobilize a joint that has been severely damaged or isthe cause of chronic pain. For example, a composition including anadhesion or fibrosis-inducing agent may be injected into an arthritic ordamaged joint to promote scarring and fixation (i.e., immobilization) ofthe joint (particularly interphalageal joints, tarsal-metatarsal joints,metacarpal joints, ankle joints, knee joints, proximal tibia-fibularjoint, hip joint, sacro-iliac joint, acromio-clavicular joint,sterno-clavicular joint and facet joints in the cervical, thoracic, andlumbar spine). In this procedure, a needle is inserted into the jointcavity, a guidewire is advanced into the joint space, a dual lumencatheter (for many of the hydrogels described below such as a materialmade from 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and methylatedcollagen such as described above, COSEAL, COSTASIS, FLOSEAL, TISSEAL,VITOSS) or a single lumen catheter (for materials such as cyanoacrylate,CORTOSS, bone cement, hydroxyapatite, calcium phosphate, calciumsulfate, hyaluronic acid, proteins, carbohydrates, sclerosing agents,and the like) is advanced over the guidewire into the articular space,the guidewire is removed, and a composition containing afibrosis-inducing agent, bone morphogenic protein(s), and/or osteogenicgrowth factor (such as transforming growth factor, platelet-derivedgrowth factor, fibroblast growth factor) is injected via the catheterinto joint until the joint space is filled. Agents such as collagenase,chymopapain, or other tissue-degrading enzymes may also be used tochemically degrade the remaining cartilage prior to, or during, theinjection of the joint-fusing composition. Over time, thefibrosis-inducing agent, bone morphogenic protein, and/or osteogenicgrowth factor can encourage fibrous ankylosis, followed by bonyankylosis of the treated joint, leading to decreased (or complete lossof) range of motion, stability, and/or reduced pain.

When performing direct injection of the joint, techniques can be used toenhance visualization of needle (or catheter) placement within the jointspace including, but not limited to, the use of a needle coated withECHO—COAT, the injection of air to enable localization by ultrasound, orthe addition of contrast agents (barium, tantalum, technitium,gadolinium, and the like) for localization by x-ray or MRI.

One method of administration, the fibrosing agent and/or osteogenicagent is delivered under direct vision during arthroscopic evaluation ofthe joint. Here the composition containing the fibrosis-inducing agent,bone morphogenic protein, and/or osteogenic growth factor is injectedinto the articular space through the side port of an arthroscope,preferably after the remaining articular cartilage has been mechanicallyor chemically debrided. In some cases, the fibrosis-inducing agent mayalso be delivered directly to the tissue during open joint fusionsurgery to enhance the efficacy of this procedure.

The injectable material may be also composed of an injectable polymersystem for use in minimally invasive joint fusion. Additionally, thepolymer system can provide sustained release of the fibrosis-inducingagent, bone morphogenic protein, and/or osteogenic growth factor toenhance efficacy and reduce the need for repeated intra-articularadministrations of active agents. The injection material suitable fordelivery of a fibrosis-inducing agent, bone morphogenic protein, and/orgrowth factor that promotes bone growth for the purposes of thisinvention can be composed of a non-degradable or a degradable material.Suitable non-degradable materials can include crosslinked compositionsthat comprise PVA, PVP, polyacrylamide, methyl methacrylate (MMA) andmethyl methacrylate styrene (MMA-styrene) which when mixed together formpolymethyl methacrylate (PMMA) or bone cement (e.g., SIMPLEX P, ZIMMERREGULAR and ZIMMER LOW VISCOSITY CEMENT, PALACOS, CMW-1 and CMW-2,ENDURANCE, synthetic cancellous bone void fillers (e.g., CORTOSS),pHEMA, poly(vinyl PEG), poly(styrene sulfonate), poly(acrylic acid),poly(methacrylic acid), as well as other polymers that are known to formhydrogels. Additional compositions include blends and copolymers of theagents listed above. Suitable degradable materials include, but are notlimited to, resorbable ceramics composed of β-tricalcium phosphate(e.g., VITOSS, PROOSTEON 500R), hydroxyapatite or Ca₁₀(PO₄)₆OH (e.g.,BIOOSS, OSTEOGRAF), calcium carbonate or CaCO₃, calcium sulfate (e.g.,OSTEOSET and ALLOMATRIX), calcium phosphate (e.g., CALCIBON or NORIANSRS), crosslinked materials of PEG, gelatin, collagen, bone allografts(e.g., ALLOGRO, ORTHOBLAST, OPTEFORM, GRAFTON), mesenchymal stem cells,hyaluronic acid, hyaluronic acid derivatives, polysaccharides,carbohydrates, proteins (e.g., albumin, casein, whey proteins, plantproteins, or fish proteins, and the like), autologous bone,demineralized bone matrix, cellulose derivatives (e.g., HPC), chitosan,chitosan derivatives, polyester-polyalkylene oxide block copolymers(e.g., PLGA-PEG-PLGA or MePEG-PLGA) and other low molecular weightpolymers that can be excreted. One material that is of particularinterest is prepared from a 4-armed thiol PEG (10K), a 4-armed NHSPEG(10K) and methylated collagen such as described above. In oneembodiment, the injectable material also contains a biologically activeagent capable of inducing fibrosis and ankylosis in the treated joint.Preferred biologically active agents include fibrosis-inducing agents,bone morphogenic proteins, and growth factors (transforming growthfactor, platelet-derived growth factor, fibroblast growth factor), whosedosages and release kinetics are all described in detail in section(iii) below.

In addition to, or in lieu of, fibrosis-inducing agents, bonemorphogenic proteins and growth factors, the injectable material can beutilized to deliver a sclerosant to the articular space. Sclerosantsinclude compounds such as ethanol, DMSO, surfactants, sucrose, NaCl,dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol,sodium tetradecyl sulfate, sodium morrhuate, sotradecol and others. Thehydrogel can further comprise agents such as glycerol, glycerin, PEG200, triethyl citrate, and triacetin as plasticizers.

The injectable materials described above can further modified to becomprised of, or contain, polymeric threads. Polymeric threads have theability to induce a fibroproliferative response from the surroundingtissue. These polymer threads can be degradable or non-degradable.Degradable threads can be composed of degradable polyesters,polyanhydrides, poly(anhydride esters), poly(ester-amides),poly(ester-ureas), polyorthoesters, polyphosphoesters, polyphosphazines,cyanoacrylate polymers, collagen, chitosan, hyaluronic acid, chromic catgut, alginates, starch, cellulose, cellulose esters, blends andcopolymers thereof, as well as other known degradable polymers.Non-degradable polymers that can be used include, but are not limitedto, polyesters (e.g., PET), polyurethanes, silicones, PE, PP, PS, PAA,PMA, silk, blends, copolymers thereof as well as others known polymers.The threads used can be composed of a single composition or composed ofa blend of differing compositions. The polymeric threads themselves canbe further modified through the addition of a polymeric coating appliedto the threads. The polymer used for coating the thread can be similarto that described above for the threads themselves. The polymer coatingmay further comprise a biologically active agent that has the ability toinduce a fibroproliferative or osteogenic response. The agents that canbe used are further described in the section (iii) below.

The injectable materials described above can be utilized to deliver aparticulate material that has the ability to induce ankylosis in thejoint. These particles can be either degradable or non-degradable andare similar to those described above for threads. In addition,particulate materials useful for the practice of this embodiment includetalc, starch, glass, silicates, silica, calcium phosphate, calciumsulfate, calcium carbonate, hydroxyapatite, synthetic mineral (VITOSSand CORTOSS), PMMA, silver nitrate, ceramic particles and otherinorganic particles known in the art to induce a fibroproliferativeresponse followed by mineralization. The particles used in thisembodiment can be all of the same composition or a blend of differingcompositions. These particles can also be used as a coating applied tothe polymeric strands as described above.

The injectable material can also be constructed such that it iscomprised of both polymeric threads and particles. The threads andparticles used are similar to those described above and may be ofuniform composition or blended composition. Virtually any combination ofthreads of differing compositions and particles of differingcompositions can be utilized in this embodiment. The hydrogel, thepolymeric threads, and the particles can all be utilized to deliver oneor more biologically active agents, as described below.

One specific composition comprises rods prepared from a methylatedcollagen-crosslinked poly(ethylene glycol) composition such as describedabove which has powdered silk particles and/or mineral particles addedto the composition prior to curing. Once deployed, the rod can absorbwater, fill the joint space and adhere to any articular cartilage orexposed bone. This expansion can prevent the rod from moving, while thepowdered and/or mineral silk can initiate an ankylosing response. As thematerial starts to degrade, the material can support the bone tissueingrowth that is initiated and potentiated by the particles. Bonemorphogenic proteins and/or growth factors (described previously andbelow) are also useful for the addition to this composition. To furtherincrease the rate of initiation of this fibroproliferative response, asclerosant such as a surfactant (SDS), ethanolamine oleate or DMSO canbe added. In addition, one may also add or replace all (or a portion) ofthe 4-armed thiol PEG with a 4-armed amino PEG. The amino PEG canprovide a gel that can take a longer time to degrade and can providesome positive charge to further attract cellular material.

A second specific embodiment consists of an injectable implant composedof silk fibers or a polymerized version of the fibrosing agent itself(i.e., repeating units of the fibrosing agent polymerized together). Theaddition of bone morphogenic proteins and/or growth factors (describedpreviously and below) is also useful for the addition to thiscomposition.

In addition to the hydrogels, bone cements, and materials containingcalcium phosphate described above, there are several other injectablecompositions suitable for use in minimally invasive joint fusionprocedures. All involve the deployment of a biomaterial into the jointspace, with or without, the addition of a fibrosis-inducing agent, bonemorphogenic protein(s), and/or a suitable growth factor(s). Thefollowing compositions can be delivered into the joint via specializeddelivery catheters, an endoscope (arthroscope; typically via asideport), a needle or other applicator, a surgically placed drain oraccess port, or other transdermal access device, includingadministration of: (a) fluids, suspensions, emulsions, microemulsions,microspheres, pastes, gels, microparticulates, sprays, aerosols, solidimplants and other formulations which release a biologically activeagent(s); (b) microparticulate silk and/or silk strands (linear,branched, and/or coiled) either alone, or loaded with an additionalfibrosis-inducing agent, bone morphogenic protein, and/or growth factorare also useful for directed injection into the joint; (c) injectablecollagen-containing formulations such as COSTASIS or materials preparedfrom a 4-armed thiol PEG (10K), a 4-armed NHS PEG (10K) and methylatedcollagen such as described above, either alone, or loaded with afibrosis-inducing agent, bone morphogenic protein, and/or growth factor,injected into the joint space; (d) injectable PEG-containingformulations such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, eitheralone, or loaded with a fibrosis-inducing agent, bone morphogenicprotein, and/or growth factor, injected into the joint space; (e)fibrinogen-containing formulations such as FLOSEAL or TISSEAL, eitheralone, or loaded with a fibrosis-inducing agent, bone morphogenicprotein, and/or growth factor, injected into the joint space; (f)hyaluronic acid-containing formulations such as RESTYLANE, HYLAFORM,PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, either alone, or loaded with afibrosis-inducing agent, bone morphogenic protein, and/or growth factorinjected into the joint space; (g) polymeric gels for surgicalimplantation such as REPEL or FLOWGEL either alone, or loaded with afibrosis-inducing agent, bone morphogenic protein, and/or growth factorinjected into the joint space; (h) orthopedic “cements” such asOSTEOBOND, LVC, SIMPLEX P, PALACOS, CORTOSS, and ENDURANCE, eitheralone, or loaded with a fibrosis-inducing agent, bone morphogenicprotein, and/or growth factor injected into the joint space; (i)surgical adhesives containing cyanoacrylates such as DERMABOND,INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II,HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or asdescribed above, either alone, or loaded with a fibrosis-inducing agent,bone morphogenic protein, and/or growth factor, injected into the jointspace; (j) surgical implants containing hydroxyapatite, calciumphosphate (such as VITOSS), or calcium sulfate, alone or loaded with afibrosis-inducing agent, bone morphogenic protein, and/or growth factor,injected into the joint space; (k) other biocompatible tissue fillers,such as those made by BioCure, 3M Company and Neomend, either alone, orloaded with a fibrosis-inducing agent, bone morphogenic protein, and/orgrowth factor, injected into the joint space; (l) polysaccharide gelssuch as the ADCON series of gels, either alone, or loaded with afibrosis-inducing agent, bone morphogenic protein, and/or growth factor,injected into the joint space; (m) films, sponges or meshes such asINTERCEED, VICRYL mesh, and GELFOAM either alone, or loaded with afibrosis-inducing agent, bone morphogenic protein, and/or growth factor,injected into the joint space; and/or (n) a hydrogel that is formed froman amino-functionalized polyethylene glycol (e.g., 4-armed tetra-aminoPEG [10k]) and a 4-armed NHS functionalized PEG (e.g., pentaerythritolpoly(ethylene glycol)ether tetra-succinimidyl glutarate [10K]). Thishydrogel may further contain collagen, methylated collagen and/orgelatin. This hydrogel can further comprise the fibrosis-inducing agentsdescribed above (e.g., silk powder or silk threads). In many of theseembodiments, it may also be useful to add a radio-opaque material (suchas tantalum, barium, other metal, or contrast material) such that theinjected material can be visualized radiographically or MRI.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agent may be utilized alone, or incombination, in the practice of this embodiment as described above.Exemplary fibrosing agents for use in minimally invasive joint fusionprocedures include talc, silk, wool, chitosan, polylysine, fibronectin,bleomycin, CTGF, bone morphogenic proteins, and/or osteogenic growthfactors (such as transforming growth factor, platelet-derived growthfactor, fibroblast growth factor) as well as analogues and derivativesof the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or a bonemorphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof).

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

The correct administration and dosage can be described further insection (c) below.

(iii) Fibrosing Agents for Minimally Invasive Joint Fusion

Exemplary fibrosing and osteogenic agents for use in minimally invasivejoint fusion include talc, silk, wool, chitosan, polylysine,fibronectin, bleomycin, CTGF, bone morphogenic proteins, and/orosteogenic growth factors (such as transforming growth factor,platelet-derived growth factor, fibroblast growth factor) as well asanalogues and derivatives of the aforementioned. In some clinicalsituations, repeated injections of the active agents described below maybe required.

The exact dose administered can vary depending upon the particular jointbeing treated. However, certain principles can be applied in theapplication of this art. Drug dose can be calculated as a function ofdose per unit volume (of the amount being injected), total drug doseadministered can be measured and appropriate surface concentrations ofactive drug can be determined. Regardless of the method of applicationof the drug to the affected joint, the exemplary fibrosing agents, bonemorphogenic proteins, and/or osteogenic growth factors (such astransforming growth factor, platelet-derived growth factor, fibroblastgrowth factor), used alone or in combination, should be administeredunder the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of talc administered into a joint in any single injectionshould not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment,the total amount of talc administered should be in the range of 10 μg to50 mg. The dose per unit volume injected should fall within the range of0.05 μg-10 μg per mm³. In one embodiment, talc is released from theinjectable such that ankylosis in the joint is promoted for a periodranging from several hours to several months. For example, talc may bereleased in effective concentrations for a period ranging from 2-12weeks. It should be readily evident given the discussions providedherein that analogues and derivatives of talc (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as talc isadministered at half the above parameters, a compound half as potent astalc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of silk delivered to the joint in any single injection shouldnot exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, thetotal amount of silk administered to the joint should be in the range of10 μg to 50 mg. The dose per unit volume injected should fall within therange of 0.05 μg-10 μg per mm³. As specific (polymeric andnon-polymeric) drug delivery vehicles can release silk at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the carrier such that a minimumconcentration of 0.01 nM to 1000 μM of silk is continuously delivered tothe tissue over the desired therapeutic time period. In one embodiment,silk is released into the joint such that ankylosis is promoted for aperiod ranging from several hours to several months. For example, silkmay be released in effective concentrations for a period ranging from2-12 weeks. It should be readily evident given the discussions providedherein that analogues and derivatives of silk (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as silk isadministered at half the above parameters, a compound half as potent assilk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of chitosan delivered into the joint should not exceed 100 mg(range of 1 μg to 100 mg). In one embodiment, the total amount ofchitosan administered into the joint in any single injection should bein the range of 10 μg to 50 mg. The dose per unit volume injected shouldfall within the range of 0.05 μg-10 μg per mm³. As specific (polymericand non-polymeric) drug delivery vehicles can release chitosan atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the carrier such thata minimum concentration of 0.01 nM to 1000 μM of chitosan iscontinuously delivered to the joint tissue. In one embodiment, chitosanis released into the joint such that ankylosis is promoted for a periodranging from several hours to several months. For example, chitosan maybe released in effective concentrations for a period ranging from 2-12weeks. It should be readily evident given the discussions providedherein that analogues and derivatives of chitosan (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent aschitosan is administered at half the above parameters, a compound halfas potent as chitosan is administered at twice the above parameters,etc.).

Utilizing polylysine as a exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of polylysine delivered into the joint in a single injectionshould not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment,the total amount of polylysine delivered to the joint should be in therange of 10 μg to 50 mg. The dose per unit volume injected should fallwithin the range of 0.05 μg-10 μg per mm³. In another embodiment,polylysine should be injected into the joint at a dose of 0.05-10μg/mm³. As specific (polymeric and non-polymeric) drug delivery vehiclescan release polylysine at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe carrier such that a minimum concentration of 0.01 nM to 1000 μM ofpolylysine is continuously delivered to the joint tissue. In oneembodiment, polylysine is administered to the joint such that ankylosisis promoted for a period ranging from several hours to several months.For example, polylysine may be released in effective concentrations fora period ranging from 2-12 weeks. It should be readily evident given thediscussions provided herein that analogues and derivatives of polylysine(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as polylysine is administered at half the above parameters, acompound half as potent as polylysine is administered at twice the aboveparameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the injectable, or administered without a polymericcarrier, the total dose of fibronectin delivered into the joint in asingle injection should not exceed 100 mg (range of 1 μg to 100 mg). Inone embodiment, the total amount of fibronectin injected into the jointshould be in the range of 10 μg to 50 mg. The dose per unit volume ofthe injection should fall within the range of 0.05 μg-10 μg per mm³. Inanother embodiment, talc should be administered at a dose of 0.05-10μg/mm³ of injected material. As specific (polymeric and non-polymeric)drug delivery vehicles can release fibronectin at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the carrier such that a minimumconcentration of 0.01 nM to 1000 μM of fibronectin is continuouslydelivered to the tissue. In one embodiment, fibronectin is released intothe joint such that ankylosis is promoted for a period ranging fromseveral hours to several months. For example, fibronectin may bereleased in effective concentrations for a period ranging from 2-12weeks. It should be readily evident given the discussions providedherein that analogues and derivatives of fibronectin (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asfibronectin is administered at half the above parameters, a compoundhalf as potent as fibronectin is administered at twice the aboveparameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of bleomycin administered to a joint in a single injectionshould not exceed 100 mg (range of 0.01 μg to 100 mg). In oneembodiment, the total amount of bleomycin injected into the joint shouldbe in the range of 0.10 μg to 50 mg. The dose per unit volume injectedshould fall within the range of 0.005 μg-10 μg per mm³. As specific(polymeric and non-polymeric) drug delivery vehicles can releasebleomycin at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from thecarrier such that a minimum concentration of 0.001 nM to 1000 μM ofbleomycin is continuously delivered to the joint. In one embodiment,bleomycin is released from the injection such that ankylosis in thejoint is promoted for a period ranging from several hours to severalmonths. For example, bleomycin may be released in effectiveconcentrations for a period ranging from 2-12 weeks. It should bereadily evident given the discussions provided herein that analogues andderivatives of bleomycin (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as bleomycin is administered at halfthe above parameters, a compound half as potent as bleomycin isadministered at twice the above parameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of CTGF administered to the joint in a single injectionshould not exceed 100 mg (range of 0.01 μg to 100 mg). In oneembodiment, the total amount of CTGF injected into the joint should bein the range of 0.10 μg to 50 mg. The dose per unit volume of theinjection should fall within the range of 0.005 μg-10 μg per mm³. Inanother embodiment, CTGF should be injected at a dose of 0.005-10μg/mm³. As specific (polymeric and non-polymeric) drug delivery vehiclescan release CTGF at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from thecarrier such that a minimum concentration of 0.001 nM to 1000 μM of CTGFis continuously delivered to the joint. In one embodiment, CTGF isreleased from the injectable such that ankylosis in the joint ispromoted for a period ranging from several hours to several months. Forexample, CTGF may be released in effective concentrations for a periodranging from 2-12 weeks. It should be readily evident given thediscussions provided herein that analogues and derivatives of CTGF (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asCTGF is administered at half the above parameters, a compound half aspotent as CTGF is administered at twice the above parameters, etc.).

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or a bonemorphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof).

Inflammatory cytokines are to be used in formulations at concentrationsthat range from 0.0001 μg/ml to approximately 20 mg/ml depending on thespecific clinical application, formulation type (e.g., gel, liquid,solid, semi-solid), formulation chemistry, duration of requiredapplication, type of medical device interface and formulation volume andor surface area coverage required. Preferably, the inflammatory cytokineis released in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof) are to be used informulations at concentrations that range from 0.001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the bone morphogenic protein is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.001μg to 500 mg); preferred 1 μg to 250 mg. When used as a device coating,the dose is per unit area of 0.001 μg-1000 μg per mm²; with a preferreddose of 0.01 μg/mm²-200 μg/mm². Minimum concentration of 10⁻⁹-10⁻⁴ M ofbone morphogenic protein is to be maintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (Example 16). The proliferative agents are to be usedin formulations at concentrations that range from 0.01 ng/mL to 25 mg/mldepending on the specific clinical application, formulation type (e.g.,gel, liquid, solid, semi-solid), formulation chemistry, duration ofrequired application, type of medical device interface and formulationvolume and or surface area coverage required. Preferably, theproliferative agent is released in effective concentrations for a periodranging from 1-180 days. The total dose for a single application istypically not to exceed 500 mg (range of 0.0001 μg to 200 mg); preferred0.001 μg to 100 mg. When used as a device coating, the dose is per unitarea of 0.00001 μg-500 μg per mm²; with a preferred dose of 0.0001μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis-inducing agents, bone morphogenicproteins, or osteogenic growth factors, or derivatives and analoguesthereof, can be utilized to create variations of the above compositionswithout deviating from the spirit and scope of the invention. It shouldalso be apparent that the agent can be utilized in a composition with orwithout polymer carrier and that altering the carrier does not deviatefrom the scope of this invention.

5. Female and Male Sterilization Devices

Permanent, highly reliable, minimally invasive methods of preventingconception are required in both men's and women's health. Although tuballigation and vasectomy have a low failure rate (approximately 1%),recently there have been advancements in making the procedures lessinvasive. This is particularly true for tubal ligation where a surgicalprocedure, either open or endoscopic, is required to “clip” thefallopian tubes. Newer implants have been designed to obstruct thefallopian tubes (or vas deferens in the male) through the non-surgicalplacement of implants that block the interior lumen of the reproductivetract. Unfortunately, since the reproductive tract is not physicallysevered (and the two ends clipped shut as in the surgical procedure),there remains the possibility that the fallopian tube (or vas deferens)can re-cannulate over time and restore fertility. The present inventionprovides compositions, implants and devices that include afibrosis-inducing agent to promote scarring of the walls of thereproductive tract in the vicinity of the implant or device. The resultis the formation of permanent scar tissue between the walls of thefallopian tube (or vas deferens) that completely obstructs the lumen,prevents the movement of the gametes through the tract, and lowers thefailure rate of the procedure (measured as the prevention of unwantedpregnancies).

(i) Permanent Female Contraceptive Devices

(a) Fallopian Tube Implants

Numerous techniques and devices are known and available to ligate orobstruct the fallopian tube such that the ovum cannot reach the uterusand conception and implantation cannot occur. As described above,surgical ligation and/or clipping of the fallopian tubes has beenconsidered the “gold standard” for permanent contraception in women formany years. Various clamps and clips for this purpose have beendescribed, including for example: a duct clamp described in U.S. Pat.No. 4,489,725; valved sterilization devices described in U.S. Pat. Nos.3,704,704 and 3,777,737; and temporary sterilization devices describedin U.S. Pat. No. 3,918,431. These devices are suitable for coating witha fibrosis-inducing agent to further enhance their effectiveness andreduce their failure rate. Unfortunately, these procedures have theobvious disadvantage of requiring placement during open or endoscopicsurgery.

However, a preferred embodiment of the present invention involvesdelivering a fibrosis-inducing agent in combination with a variety ofdevices and implants designed for placement in the fallopian tubeswithout the need for surgery. Although variable in design, all areintended to be placed transvaginally (i.e., the device or implant isinserted into the vagina, through the uterus, and placed into theinterior lumen of the fallopian tube), thus eliminating the need forsurgical access to the external (intra-abdominal/pelvic) surface of thefallopian tube via the abdomen. As a result, these implants obstruct thefallopian tube from the inside (luminal surface) and can be performed ina conscious patient in much the same manner as a gynecological exam.Examples of fallopian tube implants suitable for delivering afibrosis-inducing agent that enhances tubal occlusion include:implantable, intrafallopian, female sterilization devices (such as thosedescribed in U.S. Pat. Nos. 6,245,090; 6,068,626; and 3,675,639);occlusive wire or coil fallopian tube implants (such as those describedin U.S. Pat. No. 5,601,600); transcatheter occluding implants (such asthose described in U.S. Pat. No. 6,245,090); and fallopian tube stents(for example those described in U.S. Pat. No. 5,474,089). In addition,contraceptive uterine implants, such as intrauterine devices (IUDs), canalso be suitable for use in this embodiment.

Specific female sterilization devices (fallopian tube implants) suitablefor the delivery of one or more fibrosis-inducing agents according tothe present invention include several commercially available products.For example, the ESSURE device is a catheter-delivered stent filled withfiber (a soft micro-insert) designed to occlude the fallopian tubes(Conceptus, Inc., San Carlos, Calif.) and is described in U.S. Pat. Nos.6,176,240; 6,526,979; 5,601,600; and 5,746,769. The ECLIPSE from Ovion(Redwood City, Calif.) is a self-expanding nitinol stent filled withpolyester fibers that is delivered transvaginally via a catheter intothe fallopian tubes. Other contraceptive fallopian tube implants includeporous plastic fibers (Adiana, Redwood, Calif.) and single rod implantssuch as IMPLANON from Organon Corporation (West Orange, N.J.).

Regardless of the specific design, the aforementioned contraceptiveimplants can be adapted to release an agent which induces fibrosis oradhesion within the fallopian tube. The result can be enhanced scarringaround the implant, more complete (and permanent) filling and/orocclusion of the lumen of the fallopian tube, and a reduction in thelikelihood that female or male reproductive cells can traverse theblockade and come in contact with each other—thereby reducing theincidence of unwanted intrauterine pregnancy or tubal pregnancy.Fallopian tube implants may be adapted to have a fibrosis-inducing agentincorporated into their structure, adapted to have a surface coating ofa fibrosis-inducing agent and/or adapted to release a fibrosis-inducingagent. This can be accomplished in several manners including: (a)directly affixing to the fallopian tube implant/device a desiredfibrosis-inducing agent, or affixing a composition containing thefibrosis-inducing agent (for example, by spraying the implant with adrug and/or drug-carrier (polymeric or non-polymeric) composition tocreate a film/coating on all (or parts) of the internal and/or externalsurface of the device; by dipping the implant or device into a drugand/or drug-carrier (polymeric or non-polymeric) solution to coat all(or parts) of the device/implant; or by covalent or non-covalentattachment (such as mechanical attachment via knotting, using anadhesive, thermal treatment, electrostatic attachment, ionic attachment,hydrophobic interactions, or hydrogen bonding) of the therapeutic agentto the device/implant surface); (b) by coating the fallopian tubedevice/implant with a substance such as a hydrogel which can in turnabsorb the desired fibrosis-inducing agent or composition; (c) byinterweaving a “thread” composed of, or coated with, thefibrosis-inducing agent into the fallopian tube implant/device (e.g., apolymeric strand composed of a fibrosis-inducing agent (e.g., silk,collagen, EVA, PLA, polyurethanes, polymerized drug compositions) or athread coated with a polymer which is comprised of, or releases afibrosis-inducing agent); (d) by covering all, or portions of thefallopian tube device/implant with a sleeve, cover or mesh containing afibrosis-inducing agent (i.e., a covering comprised of afibrosis-inducing agent—polymers such as silk, collagen, EVA, PLA,polyurethanes—or polymerized compositions that release fibrosis-inducingagents); (e) constructing all, or parts of the fallopian tubeimplant/device from a fibrosis-inducing agent (e.g., constructing itfrom polymers such as silk, collagen, EVA, PLA, polyurethanes orpolymerized compositions of fibrosis-inducing agents)—which may beparticularly effective for the IMPLANON rod or the Adiana porous fibers;(f) for fallopian tube stent devices (such as the ESSURE or ECLIPSE),the central “filling” material can be composed of, or coated with, thefibrosis-inducing agent (e.g., polymeric fibers composed of afibrosis-inducing agent (e.g., silk, collagen, EVA, PLA, polyurethanes,polymerized drug compositions) or coating the fibers with a polymerwhich is comprised of, or releases a fibrosis-inducing agent); (g)otherwise impregnating the fallopian tube implant/device with thedesired fibrosis-inducing agent or composition; (h) scoring (i.e.,creating ridges or indentations) on all, or parts, of the device orimplant surface to produce irritation and ultimately fibrosis; (i)composing all, or parts, of the device or implant from metal alloys thatinduce fibrosis (e.g., copper); (j) constructing all, or parts of thedevice or implant itself from a degradable or non-degradable polymerthat releases one or more fibrosis-inducing agents—which may beparticularly effective for the IMPLANON rod, the Adiana porous fibers orthe central filling material in the ESSURE or ECLIPSE devices; and/or(k) utilizing specialized multi-drug releasing medical device systems(described, e.g., in U.S. Pat. No. 6,562,065; U.S. Patent ApplicationPublication Nos. 2003/0199970 and 2003/0167085 and in WO 03/015664 andWO 02/32347) to deliver fibrosis-inducing agents alone, or incombination.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agent may be utilized alone, or incombination, in the practice of this embodiment as described above.Exemplary fibrosing agents for use in fallopian tube implants anddevices include talc, silk, wool, chitosan, polylysine, fibronectin,bleomycin, and CTGF, as well as analogues and derivatives of theaforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or a bonemorphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, ORBMP-7 or an analogue or derivative thereof).

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

The correct administration and dosage can be described further insection (c) below.

(b) Injectable Fallopian Tube Implants

Another preferred embodiment of the present invention involvesdelivering a fibrosis-inducing agent in combination with a biomaterialdesigned for injection into the fallopian tubes to “plug” or obstructthe tube. Many different biomaterials are suitable for injection intothe fallopian tube via a transvaginal route of administration (i.e., thedelivery device is inserted into the vagina, through the uterus, placedinto the interior lumen of the fallopian tube, and the biomaterialcontaining a fibrosis-inducing agent is injected into the lumen of thefallopian tube), thus eliminating the need for surgical access to theexternal (intra-abdominal/pelvic) surface of the fallopian tube via theabdomen. As a result, these implants obstruct the fallopian tube fromthe inside (luminal surface) and can be performed in a conscious patientin much the same manner as a gynecological exam. The biomaterial canobstruct the lumen of the tube, while the fibrosis-inducing agentencourages the formation of scar tissue between the walls of thefallopian tube to permanently obstruct the lumen, prevent the movementof the gametes through the tract, and lower the failure rate of theprocedure (measured as the prevention of unwanted pregnancies).

The injectable material may be composed of a hydrogel for use in thesterilization of a mammalian female. The hydrogel can be composed of anon-degradable or a degradable material. Non-degradable materials caninclude crosslinked compositions that comprise PVA, PVP, polyacrylamide,pHEMA, poly(vinyl PEG), poly(styrene sulfonate), poly(acrylic acid),poly(methacrylic acid), as well as other polymers that are known to formhydrogels. Additional compositions include blends and copolymers of theagents listed above. Degradable materials include, but are not limitedto, crosslinked materials of PEG, gelatin, collagen, hyaluronic acid,hyaluronic acid derivatives, polysaccharides, carbohydrates, proteins(e.g., albumin, casein, whey proteins, plant proteins, and fishproteins), cellulose derivatives (e.g., HPC), chitosan, chitosanderivatives, polyester-polyalkylene oxide block copolymers (e.g.,PLGA-PEG-PLGA and MePEG-PLGA) and other low molecular weight polymersthat can be excreted. One material that is of particular interest isprepared from a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) andmethylated collagen such as described above. In a preferred embodiment,the hydrogel also contains a biologically active agent capable ofinducing fibrosis in the fallopian tube. Preferred, biologically active,fibrosis-inducing, agents, their dosages and their release kinetics, areall described in detail in section (c) below.

In addition to, or in lieu of, fibrosis-inducing agents, the hydrogelcan be utilized to deliver a sclerosant to the fallopian tube.Sclerosants include compounds such as ethanol, DMSO, surfactants,sucrose, NaCl, dextrose, glycerin, minocycline, tetracycline,doxycycline, polidocanol, sodium tetradecyl sulfate, sodium morrhuate,sotradecol and others. The hydrogel can further comprise agents such asglycerol, glycerin, PEG 200, triethyl citrate, and triacetin asplasticizers.

The hydrogels described above can further modified to be comprised of,or contain, polymeric threads. Polymeric threads have the ability toinduce a fibroproliferative response from the surrounding tissue in thefallopian tube. These polymer threads can be degradable ornon-degradable. Degradable threads can be composed of degradablepolyesters, polyanhydrides, poly(anhydride esters), poly(ester-amides),poly(ester-ureas), polyorthoesters, polyphosphoesters, polyphosphazines,cyanoacrylate polymers, collagen, chitosan, hyaluronic acid, chromic catgut, alginates, starch, cellulose, cellulose esters, blends andcopolymers thereof, as well as other known degradable polymers.Non-degradable polymers that can be used include, but are not limitedto, polyesters (e.g., PET), polyurethanes, silicones, PE, PP, PS, PAA,PMA, silk, blends, copolymers thereof as well as other known polymers.The threads used can be composed of a single composition or composed ofa blend of differing compositions. The polymeric threads themselves canbe further modified through the addition of a polymeric coating appliedto the threads. The polymer used for coating the thread can be similarto that described above for the threads themselves. The polymer coatingmay further comprise a biologically active agent that has the ability toinduce a fibroproliferative response. The agents that can be used arefurther described in the section (c) below.

The hydrogels described above can be utilized to deliver a particulatematerial that has the ability to induce a fibroproliferative response inthe fallopian tube. These particles can be either degradable ornon-degradable and are similar to those described above for threads. Inaddition to those, particulate materials useful for the practice of thisembodiment include talc, starch, glass, silicates, silica, silvernitrate, ceramic particles and other inorganic particles known in theart to induce a fibroproliferative response. The particles used in thisembodiment can be all of the same composition or a blend of differingcompositions. These particles can also be used as a coating applied tothe polymeric strands as described above.

As is readily apparent, the hydrogel can also be constructed such thatit is comprised of both polymeric threads and particles. The threads andparticles used are similar to those described above and may be ofuniform composition or blended composition. Virtually any combination ofthreads of differing compositions and particles of differingcompositions can be utilized in this embodiment. The hydrogel, thepolymeric threads, and the particles can all be utilized to deliver oneor more biologically active agents, as described below.

In a further embodiment, the hydrogel can be formed into a variety ofshapes and sizes for implantation into the fallopian tubes. For example,the hydrogel can be shaped into a rod of the desired length orsubsequently cut to the appropriate length. The hydrogel can be madeinto another shape and then further processed to form a rod of theappropriate dimensions. The rods can be cylindrical in shape or they canhave a tapered shape or an hourglass shape. The hydrogel can also beformed into a rectangular shape by adding the appropriate reagents to amould and then curing the composition. A cork-borer type device of theappropriate dimensions can be used to produce rods. The thickness of theinitial hydrogel can determine if these rods have to be further cut intothe appropriate lengths. These rods can be then dehydrated by freezedrying or by air drying. The freeze-dried rods may have more of a foamstructure while the air dried rods may be of a more solid nature. Theparticles and/or biologically active agents can be incorporated into thehydrogel prior to the curing stage. The particles can be applied to thesurface by rolling the rods in the particles or by applying theparticles to the surface by dipping, spraying or painting. The particlescan be applied in combination with a coating polymer that may dissolveor degrade. This coating polymer may be gelatin, hydroxypropylcellulose, MePEG-PLA, MePEG-polyester, polyester-PEG-polyester, or thelike.

The polymer threads can be added prior to the curing stage or they canbe added after the hydrogel has cured. The polymer threads can be addedbefore or after the drying stage of the rods. The threads may be wrappedaround the external surface of the rod. The needle may be used to passthe threads through the rod in a vertical, horizontal, diagonal manneror a combination thereof. The threads may be placed such that they formloops protruding from the surface of the rod.

One specific composition comprises rods prepared from a methylatedcollagen-crosslinked poly(ethylene glycol) composition such as describedabove which has powdered silk particles added to the composition priorto curing. Once deployed, the rod can absorb water and thereby occludethe fallopian tube. This expansion can prevent the rod from moving,while the powdered silk can initiate a fibroproliferative response. Asthe methylated collagen-crosslinked poly(ethylene glycol) compositionstarts to degrade, the material can support the fibrous tissue ingrowththat is initiated and potentiated by the silk particles. To furtherincrease the rate of initiation of this fibroproliferative response, asclerosant such as a surfactant (SDS), ethanolamine oleate or DMSO canbe added. In addition, one may also add or replace all (or a portion) ofthe 4-armed thiol PEG with a 4-armed amino PEG. The amino PEG canprovide a gel that can take a longer time to degrade and can providesome positive charge to further attract cellular material.

A second specific embodiment consists of an implant composed of silkfibers or from a polymerized version of the fibrosing agent itself(i.e., repeating units of the fibrosing agent polymerized together).

In addition to the hydrogels and related implants described above, thereare several other ways to practice this embodiment. All involve thedeployment of a biomaterial into the lumen of the fallopian tube with orwithout the addition of a fibrosis-inducing agent. The practice of thisembodiment can be performed in several ways including: (a) topicalapplication of the fibrosing agent onto the luminal surface of thefallopian tube (particularly useful for this embodiment is the use ofpolymeric carriers which release the fibrosing agent over a periodranging from several hours to several weeks—fluids, suspensions,emulsions, microemulsions, microspheres, pastes, gels,microparticulates, sprays, aerosols, solid implants and otherformulations which release a fibrosing agent can be delivered into thefallopian tube via specialized delivery catheters or other applicators);(b) microparticulate silk and/or silk strands (linear, branched, and/orcoiled), either alone, or loaded with an additional fibrosis-inducingagent are also useful for directed injection into the fallopian tube;(c) sprayable collagen-containing formulations such as COSTASIS ormaterials made from 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) andmethylated collagen such as described above, either alone, or loadedwith a fibrosis-inducing agent, applied to the lumen of the fallopiantube; (d) sprayable PEG-containing formulations such as COSEAL,FOCALSEAL, SPRAYGEL or DURASEAL, either alone, or loaded with afibrosis-inducing agent, applied to the lumen of the fallopian tube; (e)fibrinogen-containing formulations such as FLOSEAL or TISSEAL, eitheralone, or loaded with a fibrosis-inducing agent, applied to the lumen ofthe fallopian tube; (f) hyaluronic acid-containing formulations such asRESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT loaded witha fibrosis-inducing agent applied to the lumen of the fallopian tube;(g) polymeric gels for surgical implantation such as REPEL or FLOWGEL,either alone, or loaded with a fibrosis-inducing agent applied to thelumen of the fallopian tube; (h) orthopedic “cements” such as OSTEOBOND,LVC, SIMPLEX P, PALACOS, CORTOSS, and ENDURANCE, either alone, or loadedwith a fibrosis-inducing agent applied to the luminal surface of thefallopian tube; (i) surgical adhesives containing cyanoacrylates such asDERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND,TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUIDPROTECTANT or as described above, either alone, or loaded with afibrosis-inducing agent, applied to the lumen of the fallopian tube; (j)surgical implants containing hydroxyapatite, calcium phosphate (e.g.,VITOSS), or calcium sulfate, either alone, or loaded with afibrosis-inducing agent applied to the lumen of the fallopian tube; (k)other biocompatible tissue fillers, such as those made by BioCure, 3MCompany and Neomend, either alone, or loaded with a fibrosis-inducingagent, applied to the lumen of the fallopian tube; (l) polysaccharidegels such as the ADCON series of gels loaded with a fibrosis-inducingagent applied to the lumen of the fallopian tube; (m) films, sponges ormeshes such as INTERCEED, VICRYL mesh, and GELFOAM, either alone, orloaded with a fibrosis-inducing agent applied to the lumen of thefallopian tube and/or (n) a hydrogel that is formed from anamino-functionalized polyethylene glycol (e.g., 4-armed tetra-amino PEG[10k]) and a 4-armed NHS functionalized PEG (e.g., pentaerythritolpoly(ethylene glycol)ether tetra-succinimidyl glutarate [10K]). Thishydrogel may further contain collagen, methylated collagen and/orgelatin. This hydrogel can further comprise the fibrosis-inducing agentsdescribed above (e.g., silk powder or silk threads).

In many of the embodiments described above it may also be useful to adda radio-opaque material (such as tantalum, technetium, gadolinium,barium, other metal, or contrast material) such that the injectedmaterial can be visualized radiographically or MRI. The contrast agentmay be a water soluble or water insoluble radio-opaque material.Alternatively the gel or the coated implant can contain air bubbles(e.g., ECHO-COAT) or air can be injected into the tube such thatvisualization by ultrasound is enhanced.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agent may be utilized alone, or incombination, in the practice of this embodiment as described above.Exemplary fibrosing agents for use in fallopian tube implants anddevices include talc, silk, wool, chitosan, polylysine, fibronectin,bleomycin, and CTGF, as well as analogues and derivatives of theaforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone).

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

The correct administration and dosage can be described further insection (c) below.

(c) Fibrosing Agents for Fallopian Tube Implants

As fallopian tube implants are made in a variety of configurations andsizes, the exact dose administered can vary with device size, surfacearea and design. However, certain principles can be applied in theapplication of this art. Drug dose can be calculated as a function ofdose per unit area (of the portion of the device being coated), totaldrug dose administered can be measured and appropriate surfaceconcentrations of active drug can be determined. Regardless of themethod of application of the drug to the sterilization device, theexemplary fibrosing agents, used alone or in combination, should beadministered under the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of talc deliveredfrom a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of talc released from theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of talc as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, talc should beapplied to a sterilization device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. In one embodiment, talc is released fromthe surface of a sterilization device such that fibrosis in the tissueis promoted for a period ranging from several hours to several months.For example, talc may be released in effective concentrations for aperiod ranging from 1 hour-30 days. It should be readily evident giventhe discussions provided herein that analogues and derivatives of talc(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as talc is administered at half the above parameters, a compoundhalf as potent as talc is administered at twice the above parameters,etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of silk deliveredfrom a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of silk released from theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of silk as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, silk should beapplied to a sterilization device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can release silk atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the sterilizationdevice such that a minimum concentration of 0.01 nM to 1000 μM of silkis delivered to the tissue. In one embodiment, silk is released from thesurface of a sterilization device such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, silk may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of silk (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent assilk is administered at half the above parameters, a compound half aspotent as silk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of chitosandelivered from a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of chitosan released from theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of chitosan as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, chitosan should beapplied to a sterilization device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can release chitosanat differing rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the sterilizationdevice such that a minimum concentration of 0.01 nM to 1000 μM ofchitosan is delivered to the tissue. In one embodiment, chitosan isreleased from the surface of a sterilization device such that fibrosisin the tissue is promoted for a period ranging from several hours toseveral months. For example, chitosan may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of chitosan (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as chitosan is administered at halfthe above parameters, a compound half as potent as chitosan isadministered at twice the above parameters, etc.).

Utilizing polylysine as a exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of polylysinedelivered from a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of polylysine released from theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of polylysine as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, polylysine should beapplied to a sterilization device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can releasepolylysine at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from thesterilization device such that a minimum concentration of 0.01 nM to1000 μM of polylysine is delivered to the tissue. In one embodiment,polylysine is released from the surface of a sterilization device suchthat fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, polylysine may be releasedin effective concentrations for a period ranging from 1 hour-30 days. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of polylysine (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as polylysine isadministered at half the above parameters, a compound half as potent aspolylysine is administered at twice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of fibronectindelivered from a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of fibronectin released fromthe prosthesis should be in the range of 10 μg to 50 mg. The dose perunit area of the device (i.e., the dosage of fibronectin as a functionof the surface area of the portion of the device to which drug isapplied and/or incorporated) should fall within the range of 0.05 μg-10μg per mm² of surface area coated. In another embodiment, fibronectinshould be applied to a sterilization device surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease fibronectin at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe sterilization device such that a minimum concentration of 0.01 nM to1000 μM of fibronectin is delivered to the tissue. In one embodiment,fibronectin is released from the surface of a sterilization device suchthat fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, fibronectin may bereleased in effective concentrations for a period ranging from 1 hour-30days. It should be readily evident given the discussions provided hereinthat analogues and derivatives of fibronectin (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as fibronectin isadministered at half the above parameters, a compound half as potent asfibronectin is administered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of bleomycindelivered from a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 0.01 μg to 100mg). In one embodiment, the total amount of bleomycin released from theprosthesis should be in the range of 0.10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of bleomycin as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.005 μg-10 μg permm² of surface area coated. In another embodiment, bleomycin should beapplied to a sterilization device surface at a dose of 0.005 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can releasebleomycin at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from thesterilization device such that a minimum concentration of 0.001 nM to1000 μM of bleomycin is delivered to the tissue. In one embodiment,bleomycin is released from the surface of a sterilization device suchthat fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, bleomycin may be releasedin effective concentrations for a period ranging from 1 hour-30 days. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of bleomycin (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as bleomycin isadministered at half the above parameters, a compound half as potent asbleomycin is administered at twice the above parameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of CTGF deliveredfrom a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 0.01 μg to 100mg). In one embodiment, the total amount of CTGF released from theprosthesis should be in the range of 0.10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of CTGF as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.005 μg-10 μg permm² of surface area coated. In another embodiment, CTGF should beapplied to a sterilization device surface at a dose of 0.005 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can release CTGF atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the a sterilizationdevice such that a minimum concentration of 0.001 nM to 1000 μM of CTGFis delivered to the tissue. In one embodiment, CTGF is released from thesurface of a sterilization device such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, CTGF may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of CTGF (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asCTGF is administered at half the above parameters, a compound half aspotent as CTGF is administered at twice the above parameters, etc.).

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone). Inflammatorycytokines are to be used in formulations at concentrations that rangefrom 0.0001 μg/ml to approximately 20 mg/ml depending on the specificclinical application, formulation type (e.g., gel, liquid, solid,semi-solid), formulation chemistry, duration of required application,type of medical device interface and formulation volume and or surfacearea coverage required. Preferably, the inflammatory cytokine isreleased in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (Example 16). The proliferative agents are to be usedin formulations at concentrations that range from 0.01 ng/ml to 25 mg/mldepending on the specific clinical application, formulation type (e.g.,gel, liquid, solid, semi-solid), formulation chemistry, duration ofrequired application, type of medical device interface and formulationvolume and or surface area coverage required. Preferably, theproliferative agent is released in effective concentrations for a periodranging from 1-180 days. The total dose for a single application istypically not to exceed 500 mg (range of 0.0001 μg to 200 mg); preferred0.001 μg to 100 mg. When used as a device coating, the dose is per unitarea of 0.00001 μg-500 μg per mm²; with a preferred dose of 0.0001μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

(ii) Male Permanent Contraceptive Devices

For permanent contraception in men, vasectomy is a commonly used, highlyeffective method for the control of fertility. A common vasectomyprocedure involves injecting local anesthetic alongside the vasdeferens, opening the scrotum with pointed dissecting forceps, pullingthe vas through the puncture, and occluding or cutting the vas deferens(e.g., using a ligation technique in which the vas is ligatured at oneor both ends with a suture, application of an implantable clip, or bycutting and/or cauterizing the vas).

(a) Deferens Implants

Several devices for male contraception have been disclosed includingvalved sterilization devices for surgical insertion within the vasdeferens described in U.S. Pat. Nos. 3,704,704 and 3,777,737, areversible male sterilization device described in U.S. Pat. No.4,682,592, and vasectomy and Intra-Vas devices described in U.S. Pat.Nos. 3,589,355 and 4,200,088, 3,648,683, and 3,589,355. Commerciallyavailable vasectomy clips include those produced by Advanced MeditechInternational, Inc. (Flushing, N.Y.) and the VASCLIP from VMBC, LLC(Roseville, Minn.) In the present invention, the incorporation of afibrosis-inducing agent onto or into vasectomy sutures, clips, orimplantable devices (such as those described above) can promote fibrosisof the vas deferens, produce a more complete occlusion, and increase thesuccess rate of the procedure.

For clips, sutures, and other implanted devices, there are severalmethods available for incorporating fibrosing compositions onto or intothe vas deferens implant, including: (a) directly affixing to the devicea fibrosing composition (e.g., by either a spraying process or dippingprocess as described above, with or without a carrier); (b) directlyincorporating into the device a fibrosing composition (e.g., by either aspraying process or dipping process as described above, with or withouta carrier); (c) by coating the device with a substance such as ahydrogel which can in turn absorb the fibrosing composition; (d) byinterweaving into the device structure a thread coated with afibrosis-inducing agent (or the fibrosis agent-polymer compositionitself is formed into a thread); (e) by inserting the device into asleeve or mesh which is comprised of, or coated with, a fibrosingcomposition; (f) constructing the device itself (or a portion of thedevice) with a fibrosing composition; or (g) by covalently binding thefibrosing agent directly to the device surface or to a linker (smallmolecule or polymer) that is coated or attached to the device surface.

In addition to coating the device with the fibrosing composition, thefibrosing agent can be mixed with the materials that are used to makethe device such that the fibrosing agent is incorporated into the finalstructure of device itself.

In another embodiment, a film or mesh that further comprises afibrosis-inducing agent can be wrapped around the vas deferens or a cutportion of the vas deferens. This can promote fibrosis of the cut vasdeferens and can increase the success rate of the procedure. In anotherembodiment, the fibrosis-inducing agent can be incorporated into an insitu forming gel composition. Following the application of a clip,ligation with a suture, or cutting of the vas deferens, the in situforming composition can be applied to the treatment site (e.g., the cutend of the vas deferens) so as to promote fibrosis and increase thesuccess rate of the procedure.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agent may be utilized alone, or incombination, in the practice of this embodiment as described above.Exemplary fibrosing agents for use in vas deferens implants and devicesinclude talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin,and CTGF, as well as analogues and derivatives of the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone).

Furthermore, the device may additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

The correct administration and dosage can be described further insection (c) below.

(b) Injectable Vas Deferens Implants

A particularly preferred embodiment of the present invention involvespercutaneous delivery of a fibrosis-inducing agent in combination with abiomaterial designed for injection into the vas deferens to “plug” orobstruct the male reproductive tract. The vas deferens is located bypalpation (on both sides), a needle is inserted into the lumen, aguidewire is advanced into the lumen of the vas deferens, a dual lumencatheter (for many of the hydrogels described below such as materialsprepared from a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) andmethylated collagen such as described above, COSEAL, COSTASIS, FLOSEAL,TISSEAL) or a single lumen catheter (for materials such ascyanoacrylate, hyaluronic acid, proteins, carbohydrates, sclerosingagents etc.) is advanced over the guidewire into the lumen of the vasdeferens, the guidewire is removed, and a composition containing afibrosis-inducing agent is injected via the catheter into the vasdeferens until the lumen is completely occluded. Techniques can be usedto enhance visualization of needle (or catheter) placement within thevas deferens including, but not limited to, the use of a needle coatedwith ECHO—COAT or the injection of air to enable localization byultrasound, or the addition of contrast agents (e.g., barium, tantalum,technitium, gadolinium) for localization by x-ray or MRI. The injectableimplant can obstruct the vas deferens from the inside (luminal surface)and can be implanted in a conscious patient through a single (left andright) needle puncture-reducing the time required to perform theprocedure, the invasiveness (a surgical incision is not required), andthe risk of infection. The biomaterial physically obstructs the lumen ofthe tube, while the fibrosis-inducing agent encourages the formation ofscar tissue between adjacent walls of the vas deferens, leading topermanent obstruction of the lumen. This prevents the movement of spermcells through the male reproductive tract, and can lower the failurerate of the procedure (measured as the prevention of unwantedpregnancies).

The injectable material may be composed of a hydrogel for use in thesterilization of a mammalian male. The hydrogel can be composed of anon-degradable or a degradable material. Non-degradable materials caninclude crosslinked compositions that comprise PVA, PVP, polyacrylamide,pHEMA, poly(vinyl PEG), poly(styrene sulfonate), poly(acrylic acid),poly(methacrylic acid), as well as other polymers that are known to formhydrogels. Additional compositions include blends and copolymers of theagents listed above. Degradable materials include, but are not limitedto, crosslinked materials of PEG, gelatin, collagen, hyaluronic acid,hyaluronic acid derivatives, polysaccharides, carbohydrates, proteins(e.g., albumin, casein, whey proteins, plant proteins, and fishproteins), cellulose derivatives (e.g., HPC), chitosan, chitosanderivatives, polyester-polyalkylene oxide block copolymers (e.g.,PLGA-PEG-PLGA and MePEG-PLGA, etc) and other low molecular weightpolymers that can be excreted. One material that is of particularinterest is prepared from a 4-armed thiol PEG (10K), a 4-armed NHSPEG(10K) and methylated collagen such as described above. The hydrogelmay also contain a biologically active agent capable of inducingfibrosis in the vas deferens. Preferred, biologically active,fibrosis-inducing, agents, their dosages and their release kinetics, areall described in detail in section (c) below.

In addition to, or in lieu of, fibrosis-inducing agents, the hydrogelcan be utilized to deliver a sclerosant to the vas deferens. Sclerosantsinclude compounds such as ethanol, DMSO, surfactants, sucrose, NaCl,dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol,sodium tetradecyl sulfate, sodium morrhuate, sotradecol and others. Thehydrogel can further comprise agents such as glycerol, glycerin, PEG200, triethyl citrate, and triacetin as plasticizers.

The hydrogels described above can further modified to be comprised of,or contain, polymeric threads. Polymeric threads have the ability toinduce a fibroproliferative response from the surrounding tissue in thevas deferens. These polymer threads can be degradable or non-degradable.Degradable threads can be composed of degradable polyesters,polyanhydrides, poly(anhydride esters), poly(ester-amides),poly(ester-ureas), polyorthoesters, polyphosphoesters, polyphosphazines,cyanoacrylate polymers, collagen, chitosan, hyaluronic acid, chromic catgut, alginates, starch, cellulose, cellulose esters, blends andcopolymers thereof, as well as other known degradable polymers.Non-degradable polymers that can be used include, but are not limitedto, polyesters (e.g., PET), polyurethanes, silicones, PE, PP, PS, PAA,PMA, silk, blends, copolymers thereof as well as other known polymers.The threads used can be composed of a single composition or composed ofa blend of differing compositions. The polymeric threads themselves canbe further modified through the addition of a polymeric coating appliedto the threads. The polymer used for coating the thread can be similarto that described above for the threads themselves. The polymer coatingmay further comprise a biologically active agent that has the ability toinduce a fibroproliferative response. The agents that can be used arefurther described in the section (c) below.

The hydrogels described above can be utilized to deliver a particulatematerial that has the ability to induce a fibroproliferative response inthe vas deferens. These particles can be either degradable ornon-degradable and are similar to those described above for threads. Inaddition to those, particulate materials useful for the practice of thisembodiment include talc, starch, glass, silicates, silica, silvernitrate, ceramic particles and other inorganic particles known in theart to induce a fibroproliferative response. The particles used in thisembodiment can be all of the same composition or a blend of differingcompositions. These particles can also be used as a coating applied tothe polymeric strands as described above.

The hydrogel can also be constructed such that it is comprised of bothpolymeric threads and particles. The threads and particles used aresimilar to those described above and may be of uniform composition orblended composition. Virtually any combination of threads of differingcompositions and particles of differing compositions can be utilized inthis embodiment. The hydrogel, the polymeric threads, and the particlescan all be utilized to deliver one or more biologically active agents,as described below.

One specific composition comprises rods prepared from a methylatedcollagen-crosslinked poly(ethylene glycol) composition such as describedabove which has powdered silk particles added to the composition priorto curing. Once deployed, the rod can absorb water and thereby occludethe vas deferens. This expansion can prevent the rod from moving, whilethe powdered silk can initiate a fibroproliferative response. As themethylated collagen-crosslinked poly(ethylene glycol) material starts todegrade, the material can support the fibrous tissue ingrowth that isinitiated and potentiated by the silk particles. To further increase therate of initiation of this fibroproliferative response, a sclerosantsuch as a surfactant (SDS), ethanolamine oleate or DMSO can be added. Inaddition, one may also add or replace all (or a portion) of the 4-armedthiol PEG with a 4-armed amino PEG. The amino PEG can provide a gel thatcan take a longer time to degrade and can provide some positive chargeto further attract cellular material.

Another embodiment consists of an injectable implant composed of silkfibers or from a polymerized version of the fibrosing agent itself(i.e., repeating units of the fibrosing agent polymerized together).

In addition to the hydrogels and related implants described above, thereare several other ways to practice this embodiment. All involve thedeployment of a biomaterial into the lumen of the vas deferens, with orwithout, the addition of a fibrosis-inducing agent. The practice of thisembodiment can be performed in several ways including: (a) injection ofthe fibrosing agent onto the luminal surface of the vas deferens(particularly useful for this embodiment is the use of polymericcarriers which release the fibrosing agent over a period ranging fromseveral hours to several weeks-fluids, suspensions, emulsions,microemulsions, microspheres, pastes, gels, microparticulates, sprays,aerosols, solid implants and other formulations which release afibrosing agent can be delivered into the vas deferens via specializeddelivery catheters or other applicators); (b) microparticulate silkand/or silk strands (linear, branched, and/or coiled) either alone, orloaded with an additional fibrosis-inducing agent are also useful fordirected injection into the vas deferens; (c) injectablecollagen-containing formulations such as COSTASIS or materials preparedfrom a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and methylatedcollagen such as described above, either alone, or loaded with afibrosis-inducing agent, injected into the lumen of the vas deferens;(d) injectable PEG-containing formulations such as COSEAL, FOCALSEAL,SPRAYGEL or DURASEAL, either alone, or loaded with a fibrosis-inducingagent, injected into the lumen of the vas deferens; (e)fibrinogen-containing formulations such as FLOSEAL or TISSEAL, eitheralone, or loaded with a fibrosis-inducing agent, injected into the lumenof the vas deferens; (f) hyaluronic acid-containing formulations such asRESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, eitheralone, or loaded with a fibrosis-inducing agent injected into the lumenof the vas deferens; (g) polymeric gels for surgical implantation suchas REPEL or FLOWGEL either alone, or loaded with a fibrosis-inducingagent injected into the lumen of the vas deferens; (h) orthopedic“cements” such as OSTEOBOND, LVC, SIMPLEX P, PALACOS, CORTOSS, andENDURANCE, either alone, or loaded with a fibrosis-inducing agentinjected into the luminal surface of the vas deferens; (i) surgicaladhesives containing cyanoacrylates such as DERMABOND, INDERMIL,GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYLBLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or as described above,either alone, or loaded with a fibrosis-inducing agent, injected intothe lumen of the vas deferens; (j) surgical implants containinghydroxyapatite such as VITOSS (Orthovita) or calcium sulfate, alone orloaded with a fibrosis-inducing agent injected into the lumen of the vasdeferens; (k) other biocompatible tissue fillers, such as those made byBioCure, 3M Company and Neomend, either alone, or loaded with afibrosis-inducing agent, injected into the lumen of the vas deferens;(l) polysaccharide gels such as the ADCON series of gels, either alone,or loaded with a fibrosis-inducing agent injected into the lumen of thevas deferens; (m) films, sponges or meshes such as INTERCEED, VICRYLmesh, and GELFOAM either alone, or loaded with a fibrosis-inducing agentinjected into the lumen of the vas deferens; and/or (n) a hydrogel thatis formed from an amino-functionalized polyethylene glycol (e.g.,4-armed tetra-amino PEG [10k]) and a 4-armed NHS functionalized PEG(e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidylglutarate [10K]). This hydrogel may further contain collagen, methylatedcollagen and/or gelatin. This hydrogel can further comprise thefibrosis-inducing agents described above (e.g., silk powder or silkthreads).

In many of the embodiments described above it may also be useful to adda radio-opaque material (such as tantalum, barium, other metal, orcontrast material) such that the injected material can be visualizedradiographically or by MRI. The contrast agent may be a water soluble orwater insoluble radio-opaque material.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agent may be utilized alone, or incombination, in the practice of this embodiment as described above.Exemplary fibrosing agents for use in vas deferens implants and devicesinclude talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin,and CTGF, as well as analogues and derivatives of the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone).

Furthermore, the device may additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

The correct administration and dosage can be described further insection (c) below.

(c) Fibrosing Agents for Vas Deferens Implants

As vas deferens implantables and injectables are made in a variety ofconfigurations and sizes, the exact dose administered can vary withdevice size, surface area and design. However, certain principles can beapplied in the application of this art. Drug dose can be calculated as afunction of dose per unit area (of the portion of the device beingcoated), total drug dose administered can be measured and appropriatesurface concentrations of active drug can be determined. Regardless ofthe method of application of the drug to the sterilization device, theexemplary fibrosing agents, used alone or in combination, should beadministered under the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of talc deliveredfrom a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of talc released from theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of talc as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, talc should beapplied to a sterilization device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. In one embodiment, talc is released fromthe surface of a sterilization device such that fibrosis in the tissueis promoted for a period ranging from several hours to several months.For example, talc may be released in effective concentrations for aperiod ranging from 1 hour-30 days. It should be readily evident giventhe discussions provided herein that analogues and derivatives of talc(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as talc is administered at half the above parameters, a compoundhalf as potent as talc is administered at twice the above parameters,etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of silk deliveredfrom a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of silk released from theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of silk as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, silk should beapplied to a sterilization device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can release silk atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the sterilizationdevice such that a minimum concentration of 0.01 nM to 1000 μM of silkis delivered to the tissue. In one embodiment, silk is released from thesurface of a sterilization device such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, silk may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of silk (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent assilk is administered at half the above parameters, a compound half aspotent as silk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of chitosandelivered from a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of chitosan released from theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of chitosan as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, chitosan should beapplied to a sterilization device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can release chitosanat differing rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the sterilizationdevice such that a minimum concentration of 0.01 nM to 1000 μM ofchitosan is delivered to the tissue. In one embodiment, chitosan isreleased from the surface of a sterilization device such that fibrosisin the tissue is promoted for a period ranging from several hours toseveral months. For example, chitosan may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of chitosan (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as chitosan is administered at halfthe above parameters, a compound half as potent as chitosan isadministered at twice the above parameters, etc.).

Utilizing polylysine as a exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of polylysinedelivered from a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of polylysine released from theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of polylysine as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, polylysine should beapplied to a sterilization device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can releasepolylysine at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from thesterilization device such that a minimum concentration of 0.01 nM to1000 μM of polylysine is delivered to the tissue. In one embodiment,polylysine is released from the surface of a sterilization device suchthat fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, polylysine may be releasedin effective concentrations for a period ranging from 1 hour-30 days. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of polylysine (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as polylysine isadministered at half the above parameters, a compound half as potent aspolylysine is administered at twice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of fibronectindelivered from a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of fibronectin released fromthe prosthesis should be in the range of 10 μg to 50 mg. The dose perunit area of the device (i.e., the dosage of fibronectin as a functionof the surface area of the portion of the device to which drug isapplied and/or incorporated) should fall within the range of 0.05 μg-10μg per mm² of surface area coated. In another embodiment, fibronectinshould be applied to a sterilization device surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease fibronectin at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe sterilization device such that a minimum concentration of 0.01 nM to1000 μM of fibronectin is delivered to the tissue. In one embodiment,fibronectin is released from the surface of a sterilization device suchthat fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, fibronectin may bereleased in effective concentrations for a period ranging from 1 hour-30days. It should be readily evident given the discussions provided hereinthat analogues and derivatives of fibronectin (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as fibronectin isadministered at half the above parameters, a compound half as potent asfibronectin is administered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of bleomycindelivered from a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 0.01 μg to 100mg). In one embodiment, the total amount of bleomycin released from theprosthesis should be in the range of 0.10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of bleomycin as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.005 μg-10 μg permm² of surface area coated. In another embodiment, bleomycin should beapplied to a sterilization device surface at a dose of 0.005 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can releasebleomycin at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from thesterilization device such that a minimum concentration of 0.001 nM to1000 μM of bleomycin is delivered to the tissue. In one embodiment,bleomycin is released from the surface of a sterilization device suchthat fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, bleomycin may be releasedin effective concentrations for a period ranging from 1 hour-30 days. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of bleomycin (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as bleomycin isadministered at half the above parameters, a compound half as potent asbleomycin is administered at twice the above parameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, incorporated into an injectable, orapplied without a polymeric carrier, the total dose of CTGF deliveredfrom a sterilization device, or coated onto the surface of asterilization device, should not exceed 100 mg (range of 0.01 μg to 100mg). In one embodiment, the total amount of CTGF released from theprosthesis should be in the range of 0.10 μg to 50 mg. The dose per unitarea of the device (i.e., the dosage of CTGF as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.005 μg-10 μg permm² of surface area coated. In another embodiment, CTGF should beapplied to a sterilization device surface at a dose of 0.005 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can release CTGF atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the a sterilizationdevice such that a minimum concentration of 0.001 nM to 1000 μM of CTGFis delivered to the tissue. In one embodiment, CTGF is released from thesurface of a sterilization device such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, CTGF may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of CTGF (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asCTGF is administered at half the above parameters, a compound half aspotent as CTGF is administered at twice the above parameters, etc.).

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone). Inflammatorycytokines are to be used in formulations at concentrations that rangefrom 0.0001 μg/ml to approximately 20 mg/ml depending on the specificclinical application, formulation type (e.g., gel, liquid, solid,semi-solid), formulation chemistry, duration of required application,type of medical device interface and formulation volume and or surfacearea coverage required. Preferably, the inflammatory cytokine isreleased in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (Example 16). The proliferative agents are to be usedin formulations at concentrations that range from 0.01 ng/ml to 25 mg/mldepending on the specific clinical application, formulation type (e.g.,gel, liquid, solid, semi-solid), formulation chemistry, duration ofrequired application, type of medical device interface and formulationvolume and or surface area coverage required. Preferably, theproliferative agent is released in effective concentrations for a periodranging from 1-180 days. The total dose for a single application istypically not to exceed 500 mg (range of 0.0001 μg to 200 mg); preferred0.001 μg to 100 mg. When used as a device coating, the dose is per unitarea of 0.00001 μg-500 μg per mm²; with a preferred dose of 0.0001μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

6. Urinary Incontinence

The present invention provides compositions and devices for use in themanagement of urinary incontinence. Urinary incontinence, or theinvoluntary loss of urine, is a common medical condition which affects20% of women and 1-2% of men at some point in their lifetime. The mostcommon form of incontinence is stress incontinence, or the inadvertentleakage of urine in response to activities that cause an increase inintraabdominal pressure (such as sneezing, coughing, or straining). Thisoccurs when intravesical pressure (pressure in the bladder) exceeds thepressure in the urethra, forcing urine from the bladder and into theurethra in the absence of detrusor (bladder muscle) contraction. Severalconditions are thought to result in stress incontinence, including: (1)descent of the bladder neck and internal urethral sphincter out of theabdomen; and (2) intrinsic urethral sphincter failure due to trauma,surgery, childbirth or malignancy. Corrective measures are aimedprincipally at supporting the proximal urethral and bladder neck withinthe abdominal cavity by surgical or non-surgical means. A secondapproach involves the use of urethral bulking agents designed toincrease urethral pressure and reduce stress incontinence.

Regardless of their composition, urethral bulking agents are designed toprovide physical support for the urethra and prevent the leakage ofurine. Unfortunately, the symptomatic relief is often only temporary formost patients and the procedure must be repeated. Biodegradableinjectable materials (such as collagen, hyaluronic acid and othersdescribed below) are absorbed by the body over time and lose theirstructural integrity—necessitating replacement of the material viarepeat injection. Non degradable materials (such as acrylics,hydroxyapatite, polymeric beads, and others described below) do notregenerate the normal structural anatomy or biomechanics of the tissuessurrounding the urethra. The addition of a fibrosis-inducing agent to aurethral bulking agent solves several of these problems. Thefibrosis-inducing agent encourages the formation of the body's ownfibrous tissue (including collagen) around the urethra. This results inthe formation of continuously sustainable connective tissue whichsupports the urethra in a manner more closely approximating normalpelvic anatomy and biomechanics. The result is a treatment that lastslonger, provides better symptomatic relief and requires fewerre-interventions.

(i) Injectable Urinary Bulking Agents Containing a Fibrosing Agent

Bulking agents for use in treating urinary incontinence which may becombined with one or more fibrosis-inducing agents according to thepresent invention, include commercially available products for themanagement of stress incontinence. CONTIGEN (purified bovine dermalglutaraldehyde crosslinked collagen dispersed in phosphate bufferedphysiologic saline at 35 mg/ml available through C.R. Bard, Billerica,Mass.) is a widely used urethral bulking agent. Other collagen basedinjectable products, including those derived from non-bovine, human, orrecombinant sources can also be utilized in this embodiment. Otherrepresentative examples of commercially available bulking agents thatcan be used to treat urinary incontinence include hydroxyapatite loadedgel (COAPATITE from BioForm Medical, Inc., San Mateo, Calif.),micronized alloderm acellular matrix (CYMETRA from LifeCell Corporation,Branchburg, N.J.), non-animal stabilized hyaluronic acid (NASHA andDEFLUX from Q-Med), pyrolytic carbon-coated micro-beads in hydrogelcontaining beta-glucan (DURASPHERE from Carbon Medical Technologies,Inc. St. Paul, Minn. and Boston Scientific Corporation, Natick, Mass.),engineered collagen fibrils (Organogenesis, Inc., Canton, Mass.), hylanpolymer (HYLAGEL URO from Genzyme), MACROPLASTIQUE (polydimethylsiloxanein hydrogel carrier) from Uroplasty, Inc. (Minneapolis, Minn.),microspheres (e.g., acrylic beads, such as those available fromBiosphere Medical, Inc. Marlborough, Mass.), urethral bulking agentscontaining silk and elastin proteins (Protein Polymer Technologies, SanDiego, Calif.), cross-linked silicon microballoon filled withbiocompatible polymer (UROVIVE from American Medical Systems,Minnetonka, Minn.), and URYX bulking agent and Embolyx fromMicrotherapeutics, Inc., San Clemente, Calif. and Genyx Medical, Inc.,Aliso Viejo, Calif. Other manufacturers of carriers suitable for use inbulking compositions include C.R. Bard, Inc. (Murray Hill, N.J.),Collagenesis, Inc. (Acton, Mass.), American Medical Systems, Mentor,Uromed Corporation (Norwood, Mass.), Boston Scientific Corporation,Johnson & Johnson (Ethicon, Inc.), Cook Group, Inc. (Bloomington, Ind.),W.L. Gore & Associates, and SURX, Inc. (Pleasonton, Calif.).

Administration of a fibrosis-agent loaded bulking agent may typically beperformed by transurethral injection. If the carrier of thefibrosis-inducing agent contains collagen, the patient should havecompleted two skin tests (conducted 2 weeks apart) to test for anallergic response prior to administration. If these tests are negative,the collagen injection containing a fibrosis-inducing agent can beadministered to the patient. A refrigerated, single use, pre-loadedsyringe agent with a fine gauge needle (23 gauge transurethral injectionneedle with a stabilizing cannula) containing 2.5 ml of the implantmaterial (the fibrosis-inducing agent and the urethral bulking agent) isused. The patient is placed in the lithotomy position and 10 ml of 2%lidocaine is inserted into the urethra for anesthesia. In women, thebladder neck is visualized cystoscopically. Via the injection port ofthe cystoscope, the needle is inserted at the 4 o'clock position, at asharp angle, 1-1.5 cm distal to the bladder neck into the plane justbeneath the bladder mucosa. The needle is then advanced with thecystoscope parallel to the long axis of the urethra until it lies justbelow the mucosa of the bladder neck. The fibrosis-inducing agent andthe urethral bulking agent is injected slowly into this site. Theprocedure is then repeated at the 8 o'clock position. Methylene blue, orother nontoxic coloring agents, can be added to the implant to assistwith visualization of the injection.

Alternatively, periurethral injection of a fibrosis-inducing agentloaded into a urethral bulking agent can also be used for the treatmentof incontinence. A refrigerated, single use, pre-loaded syringe with afine gauge needle (periurethral injection needle) containing 2.5 ml ofthe implant material (the fibrosis-inducing agent and the urethralbulking agent) is used. The patient is placed in the lithotomy position,10 ml of 2% lidocaine is inserted into the urethra for anesthesia andthe bladder neck is visualized cystoscopically (in men the urethra canalso be visualized via suprapubic cystoscopic approach). The needle isinserted transvaginally or suprapubically into the area immediatelyadjacent and lateral to the urethra. When it reaches the appropriateposition near the bladder neck (as seen cystoscopically and describedabove), the fibrosis-inducing agent loaded into a urethral bulking agentis injected slowly into this site. Methylene blue, or other nontoxiccoloring agents, can be added to the implant to assist withvisualization of the injection.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agent may be utilized (alone or incombination) with any injectable urethral bulking agent in the practiceof this invention. Exemplary fibrosing agents for use in combinationwith injectable urethral bulking agents include talc, silk, wool,chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well asanalogues and derivatives of the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or an analogue orderivative thereof.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

The correct administration and dosage can be described further insection (iii) below.

(ii) Urinary Slings Containing a Fibrosis-Inducing Agent

In another aspect, stress incontinence and weakening of the urethramuscle may be treated with a pubovaginal sling procedure. This operationcan create enough compression on the urethra to help the patient regainbladder control. Slings for treating urinary incontinence are describedin, e.g., U.S. Pat. Nos. 6,641,524; 6,592,610; 6,387,040; 6,328,686;6,306,079; 6,221,005; 6,110,101; 6,056,687; 6,042,536; and 6,042,534 andU.S. Patent Application Publication Nos. 2003/0199732A1; 2003/0149440A1;2002/0183588A1; 2002/0058959A1; and 2002/0022841 A1.

Slings for use in treating urinary incontinence which may be combinedwith one or more fibrosis-inducing agents according to the presentinvention, include numerous commercially available products. Forexample, the SUSPEND TUTOPLAST (Processed Fascia Lata sling from Mentor)and REPLIFORM Tissue Regeneration Matrix (human allograft dermalcollagen fibers from Boston Scientific Corporation (Natick, Mass.)) canbe used. Products such as FORTAGEN Surgical Mesh and GRAFTPATCH (bothfrom Organogenesis Inc., Canton, Mass.), and SURGISIS (Cook Biotech,Inc., West Lafayette, Ind.) consist of a multilaminate sheet composedprimarily of Type I collagen (usually porcine or bovine) that is used toreinforce soft tissues during operative repair. Indications includedefects of the abdominal and thoracic wall, muscle flap reinforcement,rectal and vaginal prolapse, repair of tissue flap donor sites, ostomyreinforcement, reconstruction of the pelvic floor, hernia repair, sutureline reinforcement and reconstructive purposes. Surgical slings, such asthe FORTAFLEX Surgical Sling (Organogenesis, Inc.) and the SURGISISSling are also composed predominantly of Type I Collagen (usuallyporcine or bovine) and are utilized in open urological surgeryprocedures. Indications include pubourethral support, prolapse repair(urethral, vaginal, rectal and colonic), rectoceles, cystoceles,enteroceles, mastoplexy, reconstruction of the pelvic floor, bladdersupport, sacrocolposuspension and other reconstructive procedures. Otherrepresentative examples of slings for use in the present inventioninclude Tension-Free Vaginal Tape (TVT) from Ethicon, Inc. (Somerville,N.J.), the SPARC Female Sling System (a “vaginal tape” product fromAmerican Medical Systems), the AMS Silicone-Coated Mesh Sling (AmericanMedical Systems), BIOSLING (InjecTx/ProSurg), VERITAS Collagen MatrixUrological Sling (Synovis Life Technologies, Inc., St. Paul, Minn.),slings made from PTFE, such as Gore-Tex MYCROMESH from Gore, theSTRATESIS Urethral Sling made from acellular porcine small intestinemucosa (Cook, Inc.), slings made from allograph fascia, such as theALLOSLING (Alliant Medical), and slings made from human allograftfascia, such as FASLATA Allograft Tissue (C.R. Bard). Slings can also beprepared from, e.g., polypropylene mesh (C.R. Bard), and MERSILENEpolyester fiber mesh (Ethicon, Inc.).

Numerous polymeric and non-polymeric drug delivery systems describedabove can be used to deliver fibrosis-inducing agents from urologicalslings and implants. The methods for incorporating fibrosingcompositions onto or into the urinary incontinence devices include: (a)directly affixing to the urinary incontinence implant a fibrosingcomposition (e.g., by either a spraying process or dipping process asdescribed above, with or without a carrier); (b) directly incorporatinginto the device a fibrosing composition (e.g., by either a sprayingprocess or dipping process as described above, with or without acarrier); (c) by coating the device with a substance such as a hydrogelwhich can in turn absorb the fibrosing composition; (d) by interweavingfibrosing composition coated thread (or the polymer itself formed into athread) into the device structure; (e) by inserting the device into asleeve or mesh which is comprised of or coated with a fibrosingcomposition; (f) constructing the device itself or a portion of thedevice with a fibrosing composition, or (g) by covalently binding thefibrosing agent directly to the device surface or to a linker (smallmolecule or polymer) that is coated or attached to the device surface.For these devices, the coating process can be performed in such a manneras to a) coat the exterior surfaces of the device, b) coat the interiorsurfaces of the device or c) coat all or parts of both external andinternal surface of the device.

In addition to coating the device with the fibrosing composition, thefibrosing agent can be mixed with the materials that are used to makethe device such that the fibrosing agent is incorporated into the finaldevice.

In one embodiment, fibrosis-inducing agents can be incorporated directlyinto the formulation to produce a suspension or a solution (e.g., silkpowder, bleomycin) or it can be incorporated into a secondary carrier(e.g., micelles, liposomes, microspheres, microparticles, nanospheres,microparticulates, emulsions and/or micromulsions) that is thenincorporated into the bulking composition. In another embodiment, thefibrosis-inducing agent can be electrostatically or covalently bound toone or more of the polymeric components of the in situ formingcomposition.

In another embodiment, the fibrosis-inducing agent can be incorporatedinto the bulking agent during the manufacture of the agent. For example,silk powder can be added as a reagent during the manufacture ofmicrospheres that are used as bulking agents.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in urinary incontinence devices andcompositions include talc, silk, wool, chitosan, polylysine,fibronectin, bleomycin, and CTGF, as well as analogues and derivativesof the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or an analogue orderivative thereof.

Furthermore, the device may additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

(iii) Fibrosing Agents for Use in Urinary Incontinence Implants

As urinary incontinence devices are made in a variety of configurationsand sizes (including injectable bulking agents and slings), the exactdose administered can vary with implant or device size, surface area anddesign. However, certain principles can be applied in the application ofthis art. Drug dose can be calculated as a function of dose per unitarea (of the portion of the device being coated), total drug doseadministered can be measured and appropriate surface concentrations ofactive drug can be determined. Regardless of the method of applicationof the drug to the urinary incontinence implant or device, the exemplaryfibrosing agents, used alone or in combination, should be administeredunder the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered from a urinary incontinence device, orcoated onto the surface of a urinary incontinence device, should notexceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the totalamount of talc released from the prosthesis should be in the range of 10μg to 50 mg. The dose per unit volume of the injectable urinary bulkingagent (i.e., the dosage of talc as a function of the volume of urinarybulking agent injected) should fall within the range of 0.05 μg-10 μgper mm³. In another embodiment, talc should be applied to a urinarysling incontinence device surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. In one embodiment, talc is released from a urinaryincontinence bulking agent, implant or device such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, talc may be released in effective concentrationsfor a period ranging from 1-9 months. It should be readily evident giventhe discussions provided herein that analogues and derivatives of talc(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as talc is administered at half the above parameters, a compoundhalf as potent as talc is administered at twice the above parameters,etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered from a urinary incontinence device, orcoated onto the surface of a urinary incontinence device, should notexceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the totalamount of silk released from the prosthesis should be in the range of 10μg to 50 mg. The dose per unit volume of the injectable urinary bulkingagent (i.e., the dosage of silk as a function of the volume of urinarybulking agent injected) should fall within the range of 0.05 μg-10 μgper mm³. In another embodiment, silk should be applied to a urinarysling incontinence device surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific medical devices can release silk atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the urinaryincontinence bulking agent, implant or device such that a minimumconcentration of 0.01 nM to 1000 μM of silk is delivered to the tissue.In one embodiment, silk is released from a urinary incontinence bulkingagent, implant or device such that fibrosis in the tissue is promotedfor a period ranging from several hours to several months. For example,silk may be released in effective concentrations for a period rangingfrom 1-9 months. It should be readily evident given the discussionsprovided herein that analogues and derivatives of silk (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent assilk is administered at half the above parameters, a compound half aspotent as silk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered from a urinary incontinence device,or coated onto the surface of a urinary incontinence device, should notexceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the totalamount of chitosan released from the prosthesis should be in the rangeof 10 μg to 50 mg. The dose per unit volume of the injectable urinarybulking agent (i.e., the dosage of chitosan as a function of the volumeof urinary bulking agent injected) should fall within the range of 0.05μg-10 μg per mm³. In another embodiment, chitosan should be applied to aurinary sling incontinence device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can release chitosanat differing rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the urinaryincontinence bulking agent, implant or device such that a minimumconcentration of 0.01 nM to 1000 μM of chitosan is delivered to thetissue. In one embodiment, chitosan is released from a urinaryincontinence bulking agent, implant or device such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, chitosan may be released in effectiveconcentrations for a period ranging from 1-9 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of chitosan (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as chitosan is administered at halfthe above parameters, a compound half as potent as chitosan isadministered at twice the above parameters, etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered from a urinary incontinencedevice, or coated onto the surface of a urinary incontinence device,should not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment,the total amount of polylysine released from the prosthesis should be inthe range of 10 μg to 50 mg. The dose per unit volume of the injectableurinary bulking agent (i.e., the dosage of polylysine as a function ofthe volume of urinary bulking agent injected) should fall within therange of 0.05 μg-10 μg per mm³. In another embodiment, polylysine shouldbe applied to a urinary sling incontinence device surface at a dose of0.05 μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease polylysine at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe urinary incontinence bulking agent, implant or device such that aminimum concentration of 0.01 nM to 1000 μM of polylysine is deliveredto the tissue. In one embodiment, polylysine is released from a urinaryincontinence bulking agent, implant or device such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, polylysine may be released in effectiveconcentrations for a period ranging from 1-9 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of polylysine (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as polylysine is administered at halfthe above parameters, a compound half as potent as polylysine isadministered at twice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered from a urinaryincontinence device, or coated onto the surface of a urinaryincontinence device, should not exceed 100 mg (range of 1 μg to 100 mg).In one embodiment, the total amount of fibronectin released from theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitvolume of the injectable urinary bulking agent (i.e., the dosage offibronectin as a function of the volume of urinary bulking agentinjected) should fall within the range of 0.05 μg-10 μg per mm³. Inanother embodiment, talc should be applied to a urinary slingincontinence device surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific medical devices can release fibronectinat differing rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the urinaryincontinence bulking agent, implant or device such that a minimumconcentration of 0.01 nM to 1000 μM of fibronectin is delivered to thetissue. In one embodiment, fibronectin is released from a urinaryincontinence bulking agent, implant or device such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, fibronectin may be released in effectiveconcentrations for a period ranging from 1-9 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of fibronectin (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as fibronectin is administered at halfthe above parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered from a urinary incontinencedevice, or coated onto the surface of a urinary incontinence device,should not exceed 100 mg (range of 0.01 μg to 100 mg). In oneembodiment, the total amount of bleomycin released from the prosthesisshould be in the range of 0.10 μg to 50 mg. The dose per unit volume ofthe injectable urinary bulking agent (i.e., the dosage of bleomycin as afunction of the volume of urinary bulking agent injected) should fallwithin the range of 0.005 μg-10 μg per mm³. In another embodiment,bleomycin should be applied to a urinary sling incontinence devicesurface at a dose of 0.005 μg/mm²-10 μg/mm² of surface area coated. Asspecific (polymeric and non-polymeric) drug delivery vehicles andspecific medical devices can release bleomycin at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the urinary incontinence bulking agent,implant or device such that a minimum concentration of 0.001 nM to 1000μM of bleomycin is delivered to the tissue. In one embodiment, bleomycinis released from a urinary incontinence bulking agent, implant or devicesuch that fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, bleomycin may be releasedin effective concentrations for a period ranging from 1-9 months. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of bleomycin (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as bleomycin isadministered at half the above parameters, a compound half as potent asbleomycin is administered at twice the above parameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered from a urinary incontinence device, orcoated onto the surface of a urinary incontinence device, should notexceed 100 mg (range of 0.01 μg to 100 mg). In one embodiment, the totalamount of CTGF released from the prosthesis should be in the range of0.10 μg to 50 mg. The dose per unit volume of the injectable urinarybulking agent (i.e., the dosage of CTGF as a function of the volume ofurinary bulking agent injected) should fall within the range of 0.005μg-10 μg per mm³. In another embodiment, CTGF should be applied to aurinary sling incontinence device surface at a dose of 0.005 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific medical devices can release CTGF atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the urinaryincontinence bulking agent, implant or device such that a minimumconcentration of 0.001 nM to 1000 μM of CTGF is delivered to the tissue.In one embodiment, CTGF is released from a urinary incontinence bulkingagent, implant or device such that fibrosis in the tissue is promotedfor a period ranging from several hours to several months. For example,CTGF may be released in effective concentrations for a period rangingfrom 1-9 months. It should be readily evident given the discussionsprovided herein that analogues and derivatives of CTGF (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asCTGF is administered at half the above parameters, a compound half aspotent as CTGF is administered at twice the above parameters, etc.).

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone or an analogue orderivative thereof). Inflammatory cytokines are to be used informulations at concentrations that range from 0.0001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the inflammatory cytokine is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.0001μg to 100 mg); preferred 0.001 μg to 50 mg. When used as a devicecoating, the dose is per unit area of 0.0001 μg-500 μg per mm²; with apreferred dose of 0.001 μg/mm²-200 μg/mm². Minimum concentration of10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to be maintained on thedevice surface.

Furthermore, the device may additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (Example 16). The proliferative agents are to be usedin formulations at concentrations that range from 0.1 ng/ml to 25 mg/mldepending on the specific clinical application, formulation type (e.g.,gel, liquid, solid, semi-solid), formulation chemistry, duration ofrequired application, type of medical device interface and formulationvolume and or surface area coverage required. Preferably, theproliferative agent is released in effective concentrations for a periodranging from 1-180 days. The total dose for a single application istypically not to exceed 500 mg (range of 0.0001 μg to 200 mg); preferred0.001 μg to 100 mg. When used as a device coating, the dose is per unitarea of 0.00001 μg-500 μg per mm²; with a preferred dose of 0.0001μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

7. Venous Occluding Materials Containing Fibrosing Agents

A variety of devices and injectable implants have been developed forinjection into veins for cosmetic purposes. Typically, a needle orcatheter is advanced into an unwanted vein (primarily “spider” veins orvaricose veins) and a sclerosing agent is injected into the vessel toscar the vein shut. Unfortunately, currently available agents often donot produce permanent fibrosis (true luminal scarring where the walls ofthe vessel permanently adhere to each other and fibrous tissue occludesthe vessel) leading to the possibility of recannulization,re-establishment of venous flow, and ultimately recurrence of the vein(i.e., failure of the procedure). The present invention describes theaddition of fibrosis-inducing agents to the materials injected into thevein for the purpose of producing a permanent, obstructive scar in thevascular lumen that results in regression and absorption of the unwantedvein. If venous flow is permanently prevented in the vein due toobstructive fibrosis, the body resorbs the non-functioning vessel andeliminates the vein, leaving little or no chance for recurrence.

There are several commercially available sclerosing agents that are usedto treat spider veins and varicose veins, which may be combined with oneor more fibrosis-inducing drugs according to the present invention. Forexample, Wyeth Pharmaceuticals (Collegeville, Pa.), a division of Wyeth(Madison, N.J.), sells SOTRADECOL, which is a sodium tetradecyl sulfateinjection. Other sclerosing agents available for treating spider veinsand varicose veins (and may be suitable for delivery of afibrosis-inducing agent) include sodium morrhuate, ethanolamine oleate,compositions containing ethanol, DMSO, surfactants, sucrose, NaCl,dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol,sodium tetradecyl sulfate, sodium morrhuate, sotradecol and others.Other examples of compositions suitable for cosmetic vascular injectioninclude silk (e.g., microparticulate silk), polymeric gels composed offibrosis-inducing agents (such as those available from PolymerixCorporation) and fibrosis-inducing agents loaded into vascular fillers.

A variety of polymer based products have been developed forintra-vascular injection for the purposes of arterial embolization(described in greater detail in the section 12(ii) on arterialembolization below). Many of these intra-vascular polymer systems aresuitable for the treatment of spider veins and varicose veins and can bemade more efficacious through the addition of a fibrosis-inducing agent.Examples of products suitable for combining with a fibrosis-inducingagent include, for example, TRUFILL n-butyl cyanoacrylate (n-BCA) LiquidEmbolic System (available from Cordis, a division of Johnson andJohnson, Miami, Fla.); ONYX Liquid Embolic System (Micro Therapeutics,Irvine, Calif.). Other examples of materials suitable for the deliveryof a fibrosis-inducing agent into the venous system includepolymer/solvent systems in which the solvent diffuses from the polymermatrix once it has been injected into the vein (e.g., degradablepolymeric systems from Atrix, non-degradable polymeric compositions fromONYX and EMBOLYX, and in situ forming materials from Biocure, AngiotechPharmaceuticals, Inc., 3M Company, and Neomend. Other types ofcommercially available embolic agents that can be loaded or made with afibrosis-inducing agent for venous occlusion include PVA particles (fromCook, Inc. and Angiodynamics Inc.), and microsphere formulations (e.g.,EMBOSPHERE and EMBOGOLD from Biosphere, Inc. (Rockland, Mass.) and BEADBLOCK from Biocompatibles Ltd., United Kingdom).

In one embodiment, the injectable vascular material is composed of aninjectable polymer system combined with a fibrosis-inducing agent. Oneinjectable polymer system that is of particular interest is preparedfrom a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and methylatedcollagen such as described above. The injectable vascular material maybe combined with a fibrosis-inducing agent (e.g., talc, silk, wool,chitosan, polylysine, fibronectin, bleomycin, CTGF, bone morphogenicproteins, transforming growth factor, platelet-derived growth factor,fibroblast growth factor, as well as analogues and derivatives of thesecompounds) and injected into a varicose vein or spider vein. In additionto, or in lieu of, fibrosis-inducing agents, bone morphogenic proteinsand growth factors, the injectable material can also be utilized todeliver a sclerosant to the vein. Sclerosants include compounds such asethanol, DMSO, surfactants, sucrose, sodium morrhuate, ethanolamineoleate NaCl, dextrose, glycerin, minocycline, tetracycline, doxycycline,polidocanol, sodium tetradecyl sulfate, sodium morrhuate, sotradecol andothers. The injectable material can further comprise agents such asglycerol, glycerin, PEG 200, triethyl citrate, and triacetin asplasticizers.

In another embodiment, the injectable intra-vascular materials describedabove can be further modified to be extruded from the catheter (orneedle) as a polymeric “thread” or contain polymeric threads. Polymericthreads have the ability to induce clotting as well as afibroproliferative response from the vascular wall. The injectable“threads” can be loaded with, coated with, or comprised of afibrosis-inducing agent (e.g., an injectable implant composed of silkfibers or a polymerized version of the fibrosing agent itself). Thesepolymer threads can be degradable or non-degradable. Degradable threadscan be composed of degradable polyesters, polyanhydrides, poly(anhydrideesters), poly(ester-amides), poly(ester-ureas), polyorthoesters,polyphosphoesters, polyphosphazines, cyanoacrylate polymers, collagen,chitosan, hyaluronic acid, chromic cat gut, alginates, starch,cellulose, cellulose esters, blends and copolymers thereof, as well asother known degradable polymers. Non-degradable polymers that can beused include, but are not limited to, polyesters (e.g., PET),polyurethanes, silicones, PE, PP, PS, PAA, PMA, silk, blends, copolymersthereof as well as other known polymers. The threads used can becomposed of a single composition or composed of a blend of differingcompositions. The polymeric threads themselves can be further modifiedthrough the addition of a polymeric coating applied to the threads. Thepolymer used for coating the thread can be similar to that describedabove for the threads themselves. The polymer coating may furthercomprise a biologically active fibrosis-inducing agent.

In another embodiment, the intra-vascular injectable materials describedabove can be formulated to be delivered from the catheter (or needle) asa particulate material that has the ability to induce clofting andfibrosis. The injectable particles can be loaded with, coated with, orcomprised of a fibrosis-inducing agent. These particles can be eitherdegradable or non-degradable and are similar in composition to thosedescribed above for threads. In addition to the aforementioned polymers,particulate materials useful for the practice of this embodiment includetalc, starch, glass, silicates, silica, calcium phosphate, calciumsulfate, calcium carbonate, hydroxyapatite, synthetic mineral (VITOSSand CORTOSS), PMMA, silver nitrate, ceramic particles and otherinorganic particles known in the art to induce a fibroproliferativeresponse. The particles used in this embodiment can be all of the samecomposition or a blend of differing compositions. These particles canalso be used as a coating applied to the polymeric strands as describedabove.

As is readily apparent, the injectable intravascular material can alsobe constructed such that it is comprised of both polymeric threads andparticles. The threads and particles used are similar to those describedabove and may be of uniform composition or blended composition.Virtually any combination of threads of differing compositions andparticles of differing compositions can be utilized in this embodiment.The hydrogel, the polymeric threads, and the particles can all beutilized to deliver one or more fibrosis-inducing agents.

In addition to the injectable materials described above, there areseveral other injectable compositions suitable for intra-vascularadministration in the treatment of spider veins and varicose veins. Allinvolve the deployment of a biomaterial into the lumen of the vein, withor without, the addition of a fibrosis-inducing agent, bone morphogenicprotein(s), and/or a suitable growth factor(s). The followingcompositions can be delivered into the vein via specialized deliverycatheters, an endoscope (e.g., angioscope; typically the material isdelivered via a sideport in the device), a needle or other applicator, asurgically placed access device, or other transdermal intra-vascularaccess device and include administration of: (a) fluids, suspensions,emulsions, microemulsions, microspheres, pastes, gels,microparticulates, sprays, aerosols, solid implants and otherformulations which release a biologically active agent(s); (b)microparticulate silk and/or silk strands (linear, branched, and/orcoiled) either alone, or loaded with an additional fibrosis-inducingagent, bone morphogenic protein, and/or growth factor injected into thevein; (c) injectable collagen-containing formulations such as COSTASISor materials made from 4-armed thiol PEG (10K), a 4-armed NHS PEG (10K)and methylated collagen such as described above, either alone, or loadedwith a fibrosis-inducing agent, bone morphogenic protein, and/or growthfactor, injected into the vein; (d) injectable PEG-containingformulations such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, eitheralone, or loaded with a fibrosis-inducing agent, bone morphogenicprotein, and/or growth factor, injected into the vein; (e)fibrinogen-containing formulations such as FLOSEAL or TISSEAL, eitheralone, or loaded with a fibrosis-inducing agent, bone morphogenicprotein, and/or growth factor, injected into the vein; (f) hyaluronicacid-containing formulations such as RESTYLANE, HYLAFORM, PERLANE,SYNVISC, SEPRAFILM, SEPRACOAT, either alone, or loaded with afibrosis-inducing agent, bone morphogenic protein, and/or growth factorinjected into the vein; (g) polymeric gels for surgical implantationsuch as REPEL or FLOWGEL either alone, or loaded with afibrosis-inducing agent, bone morphogenic protein, and/or growth factorinjected into the vein; (h) orthopedic “cements” such as OSTEOBOND, LVC,SIMPLEX P, PALACOS, CORTOSS, and ENDURANCE, either alone, or loaded witha fibrosis-inducing agent, bone morphogenic protein, and/or growthfactor injected into the vein; (i) surgical adhesives containingcyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND,HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASESOOTHE-N-SEAL LIQUID PROTECTANT or as described above, either alone, orloaded with a fibrosis-inducing agent, bone morphogenic protein, and/orgrowth factor, injected into the vein; (j) surgical implants containinghydroxyapatite, calcium phosphate (such as VITOSS), or calcium sulfate,alone or loaded with a fibrosis-inducing agent, bone morphogenicprotein, and/or growth factor, injected into the vein; (k) otherbiocompatible tissue fillers, such as those made by BioCure, 3M Companyand Neomend, either alone, or loaded with a fibrosis-inducing agent,bone morphogenic protein, and/or growth factor, injected into the vein;(l) polysaccharide gels such as the ADCON series of gels, either alone,or loaded with a fibrosis-inducing agent, bone morphogenic protein,and/or growth factor, injected into the vein; (m) films, sponges ormeshes such as INTERCEED, VICRYL mesh, and GELFOAM either alone, orloaded with a fibrosis-inducing agent, bone morphogenic protein, and/orgrowth factor, injected into the vein; and/or (n) a hydrogel that isformed from an amino-functionalized polyethylene glycol (e.g., 4-armedtetra-amino PEG [10k]) and a 4-armed NHS functionalized PEG (e.g.,pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate[10K]). This hydrogel may further contain collagen, methylated collagenand/or gelatin. This hydrogel can further comprise the fibrosis-inducingagents described above (e.g., silk powder or silk threads).

In many of these embodiments, it may also be useful to add aradio-opaque material (such as tantalum, barium, other metal, orcontrast material) such that the injected material can be visualizedradiographically or MRI. Also, when performing direct injection into thevein, techniques can be used to enhance visualization of needle (orcatheter) via ultrasound through the use of a needle coated withECHO—COAT or the injection of air (microbubbles).

In one preferred method of administration for the treatment of largevaricose veins, the fibrosing agent is delivered under direct visionduring angioscopic evaluation of the vessel. Here the compositioncontaining the fibrosis-inducing agent, bone morphogenic protein, and/orgrowth factor is injected into the lumen of the varicose vein throughthe side port of an angioscope. In some cases, the fibrosis-inducingagent may also be delivered directly to the lumen of the vein (or thetissue surrounding the vein) during open surgery.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agent may be utilized alone, or incombination, in the practice of this embodiment as described above.Exemplary fibrosing agents for use in venous destruction proceduresinclude talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin,CTGF, bone morphogenic proteins, and/or osteogenic growth factors (suchas transforming growth factor, platelet-derived growth factor,fibroblast growth factor) as well as analogues and derivatives of theaforementioned. In some clinical situations, repeated injections of theactive agents described below may be required.

The exact dose administered can vary depending upon the particular veinbeing treated. However, certain principles can be applied in theapplication of this art. Drug dose can be calculated as a function ofdose per unit volume (of the amount being injected), total drug doseadministered can be measured and appropriate surface concentrations ofactive drug can be determined. Regardless of the method of applicationof the drug to the vein, the exemplary fibrosing agents, bonemorphogenic proteins, and/or growth factors (such as transforming growthfactor, platelet-derived growth factor, fibroblast growth factor), usedalone or in combination, should be administered under the followingdosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of talc administered into the venous system in any singleinjection should not exceed 100 mg (range of 1 μg to 100 mg). In oneembodiment, the total amount of talc administered should be in the rangeof 10 μg to 50 mg. The dose per unit volume injected should fall withinthe range of 0.05 μg-10 μg per mm³. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific implants can releasetalc at differing rates, the above dosing parameters should be utilizedin combination with the release rate of the drug from the carrier suchthat a minimum concentration of 0.01 nM to 1000 μM of talc iscontinuously delivered to the vein over the desired therapeutic period.In one embodiment, talc is released from the injectable such thatfibrosis in the vein is promoted for a period ranging from several hoursto several months. For example, talc may be released in effectiveconcentrations for a period ranging from 2-12 weeks. It should bereadily evident given the discussions provided herein that analogues andderivatives of talc (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as talc is administered at half the aboveparameters, a compound half as potent as talc is administered at twicethe above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of silk delivered to the venous system in any singleinjection should not exceed 100 mg (range of 1 μg to 100 mg). In oneembodiment, the total amount of silk administered to the vein should bein the range of 10 μg to 50 mg. The dose per unit volume injected shouldfall within the range of 0.05 μg-10 μg per mm³. As specific (polymericand non-polymeric) drug delivery vehicles can release silk at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the carrier such that a minimumconcentration of 0.01 nM to 1000 μM of silk is continuously delivered tothe tissue over the desired therapeutic time period. In one embodiment,silk is released into the lumen of the vein such that fibrosis ispromoted for a period ranging from several hours to several months. Forexample, silk may be released in effective concentrations for a periodranging from 2-12 weeks. It should be readily evident given thediscussions provided herein that analogues and derivatives of silk (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent assilk is administered at half the above parameters, a compound half aspotent as silk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of chitosan delivered into the vein should not exceed 100 mg(range of 1 μg to 100 mg). In one embodiment, the total amount ofchitosan administered into the vein in any single injection should be inthe range of 10 μg to 50 mg. The dose per unit volume injected shouldfall within the range of 0.05 μg-10 μg per mm³. As specific (polymericand non-polymeric) drug delivery vehicles can release chitosan atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the carrier such thata minimum concentration of 0.01 nM to 1000 μM of chitosan iscontinuously delivered into the vein. In one embodiment, chitosan isreleased into the lumen of the vein such that fibrosis is promoted for aperiod ranging from several hours to several months. For example,chitosan may be released in effective concentrations for a periodranging from 2-12 weeks. It should be readily evident given thediscussions provided herein that analogues and derivatives of chitosan(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as chitosan is administered at half the above parameters, acompound half as potent as chitosan is administered at twice the aboveparameters, etc.).

Utilizing polylysine as a exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of polylysine delivered into the vein in a single injectionshould not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment,the total amount of polylysine delivered to the vein should be in therange of 10 μg to 50 mg. The dose per unit volume injected should fallwithin the range of 0.05 μg-10 μg per mm³. In another embodiment,polylysine should be injected into the vein at a dose of 0.05-10 μg/mm³.As specific (polymeric and non-polymeric) drug delivery vehicles canrelease polylysine at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe carrier such that a minimum concentration of 0.01 nM to 1000 μM ofpolylysine is continuously delivered to the vein. In one embodiment,polylysine is administered to the lumen of the vein such that fibrosisis promoted for a period ranging from several hours to several months.For example, polylysine may be released in effective concentrations fora period ranging from 2-12 weeks. It should be readily evident given thediscussions provided herein that analogues and derivatives of polylysine(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as polylysine is administered at half the above parameters, acompound half as potent as polylysine is administered at twice the aboveparameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the injectable, or administered without a polymericcarrier, the total dose of fibronectin delivered into the vein in asingle injection should not exceed 100 mg (range of 1 μg to 100 mg). Inone embodiment, the total amount of fibronectin injected into the veinshould be in the range of 10 μg to 50 mg. The dose per unit volume ofthe injection should fall within the range of 0.05 μg-10 μg per mm³. Inanother embodiment, talc should be administered at a dose of 0.05-10μg/mm³ of injected material. As specific (polymeric and non-polymeric)drug delivery vehicles can release fibronectin at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the carrier such that a minimumconcentration of 0.01 nM to 1000 μM of fibronectin is continuouslydelivered to the vein. In one embodiment, fibronectin is released intothe lumen of the vein such that fibrosis is promoted for a periodranging from several hours to several months. For example, fibronectinmay be released in effective concentrations for a period ranging from2-12 weeks. It should be readily evident given the discussions providedherein that analogues and derivatives of fibronectin (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asfibronectin is administered at half the above parameters, a compoundhalf as potent as fibronectin is administered at twice the aboveparameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of bleomycin administered to a vein in a single injectionshould not exceed 100 mg (range of 0.01 μg to 100 mg). In oneembodiment, the total amount of bleomycin injected into the vein shouldbe in the range of 0.10 μg to 50 mg. The dose per unit volume injectedshould fall within the range of 0.005 μg-10 μg per mm³. As specific(polymeric and non-polymeric) drug delivery vehicles can releasebleomycin at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from thecarrier such that a minimum concentration of 0.001 nM to 1000 μM ofbleomycin is continuously delivered to the vein. In one embodiment,bleomycin is released from the injection such that fibrosis in the veinis promoted for a period ranging from several hours to several months.For example, bleomycin may be released in effective concentrations for aperiod ranging from 2-12 weeks. It should be readily evident given thediscussions provided herein that analogues and derivatives of bleomycin(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as bleomycin is administered at half the above parameters, acompound half as potent as bleomycin is administered at twice the aboveparameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the injectable, or administered without a polymeric carrier, thetotal dose of CTGF administered to the vein in a single injection shouldnot exceed 100 mg (range of 0.01 μg to 100 mg). In one embodiment, thetotal amount of CTGF injected into the vein should be in the range of0.10 μg to 50 mg. The dose per unit volume of the injection should fallwithin the range of 0.005 μg-10 μg per mm³. In another embodiment, CTGFshould be injected at a dose of 0.005-10 μg/mm³. As specific (polymericand non-polymeric) drug delivery vehicles can release CTGF at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the carrier such that a minimumconcentration of 0.001 nM to 1000 μM of CTGF is continuously deliveredto the vein. In one embodiment, CTGF is released from the injectablesuch that fibrosis in the vein is promoted for a period ranging fromseveral hours to several months. For example, CTGF may be released ineffective concentrations for a period ranging from 2-12 weeks. It shouldbe readily evident given the discussions provided herein that analoguesand derivatives of CTGF (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as CTGF is administered at half theabove parameters, a compound half as potent as CTGF is administered attwice the above parameters, etc.).

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone). Inflammatorycytokines are to be used in formulations at concentrations that rangefrom 0.0001 μg/ml to approximately 20 mg/ml depending on the specificclinical application, formulation type (e.g., gel, liquid, solid,semi-solid), formulation chemistry, duration of required application,type of medical device interface and formulation volume and or surfacearea coverage required. Preferably, the inflammatory cytokine isreleased in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see, e.g., Example 16). The proliferative agents areto be used in formulations at concentrations that range from 0.1 ng/mlto 25 mg/ml depending on the specific clinical application, formulationtype (e.g., gel, liquid, solid, semi-solid), formulation chemistry,duration of required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis-inducing agents, bone morphogenicproteins, or osteogenic growth factors, or derivatives and analoguesthereof, can be utilized to create variations of the above compositionswithout deviating from the spirit and scope of the invention.

It should also be apparent that the agent can be utilized in acomposition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

8. Fecal Incontinence

The present invention provides compositions and devices for use in themanagement of fecal incontinence. Fecal incontinence is the inability tocontrol bowel movements. Reasons for fecal incontinence include, e.g.,damage to the nerves of the pelvic floor, trauma to the anal and/orrectal area, a birth defect, altered stool consistency, or abnormalrectal capacity, and diseases such as diabetes, multiple sclerosis andcolorectal disease. In women, fecal incontinence can be the result of adifficult childbirth.

(i) Anal Sphincter Bulking Agents

Fecal incontinence may be treated by injecting a bulking agent close tothe anal sphincter to reinforce closure of the anal sphincter. Bulkingagents which may be combined with one or more fibrosis-inducing agentsaccording to the present invention, include numerous commerciallyavailable products. For example, injectable microspheres from ArtesMedical, Inc. (San Diego, Calif.), ENTERYX (ethylene vinyl alcoholpolymer implant from Boston Scientific Corporation), and CONTIGEN(purified bovine dermal glutaraldehyde crosslinked collagen dispersed inphosphate buffered physiologic saline at 35 mg/ml available through C.R.Bard, Billerica, Mass.) are widely used bulking agents. Other collagenbased injectable products, including those derived from non-bovine,human, or recombinant sources can also be utilized in this embodiment.Additional representative examples of commercially available bulkingagents that can be used to treat fecal incontinence includehydroxyapatite loaded gel (COAPATITE), micronized alloderm acellularmatrix (CYMETRA), non-animal stabilized hyaluronic acid (NASHA)(DEFLUX), pyrolytic carbon-coated micro-beads in hydrogel containingbeta-glucan (DURASPHERE), engineered collagen fibrils (Organogenesis),hylan polymer (HYLAGEL URO), MACROPLASTIQUE (polydimethylsiloxane inhydrogel carrier), microspheres (e.g., acrylic beads, such as thoseavailable from Biosphere Medical), urethral bulking agents containingsilk and elastin proteins (such as those available from Protein PolymerTechnologies), cross-linked silicon microballoon filled withbiocompatible polymer (UROVIVE), and URYX bulking agent and Embolyx fromMicrotherapeutics, Inc., San Clemente, Calif. and Genyx Medical, Inc.,Aliso Viejo, Calif. Other manufacturers of carriers suitable for use inbulking compositions include C.R. Bard, Collagenesis, American MedicalSystems, Mentor, Uromed, Boston Scientific Corporation, Johnson &Johnson (Ethicon, Inc.), Cook Urologic, W.L. Gore, and SURx.

Regardless of their composition, bulking agents are designed to providephysical support for the anal sphincter and prevent the leakage offeces. Unfortunately, the symptomatic relief is often only temporary formost patients and the procedure must be repeated. Biodegradableinjectable materials (such as collagen, hyaluronic acid and othersdescribed above) are absorbed by the body over time and lose theirstructural integrity—necessitating replacement of the material viarepeat injection. Non-degradable materials (such as acrylics,hydroxyapatite, polymeric beads, and others described above) do notregenerate the normal structural anatomy or biomechanics of the tissuessurrounding the anal sphincter. The addition of a fibrosis-inducingagent to a bulking agent can solve several of these problems. Thefibrosis-inducing agent can encourage the formation of the body's ownfibrous tissue (including collagen) around the anal sphincter. Thisresults in the formation of continuously sustainable connective tissuewhich supports the anal sphincter in a manner more closely approximatingnormal rectal anatomy and biomechanics. The result is a treatment thatlasts longer, provides better symptomatic relief and requires fewerre-interventions.

In one aspect, the present invention provides injectable compositions(bulking agents) for use in treating fecal incontinence. Specifically,the fibrosis-inducing agent can be produced with or without a carrier(such as collagen, hyaluronic acid, and/or another biocompatiblepolymer) which is then injected in and around the anal sphincter toprovide support and continence. In one embodiment, fibrosis-inducingagents can be incorporated directly into the formulation to produce asuspension or a solution (e.g., silk powder, bleomycin) or it can beincorporated into a secondary carrier (e.g., micelles, liposomes,microspheres, microparticies, nanospheres, microparticulates, emulsions,and/or microemulsions) that is then incorporated into the bulkingcomposition. In another embodiment, the fibrosis-inducing agent can beelectrostatically or covalently bound to one or more of the polymericcomponents of the in situ forming composition. Injection of the bulkingagent (many commercial examples of which were described above)containing the fibrosing agent into the perimuscular space (alone or incombination with a polymeric carrier) can enhance scarring and supportto the anal sphincter and may result in endogenous collagen production.

In another embodiment, the fibrosis-inducing agent can be incorporatedinto the bulking agent during the manufacture of the agent. For example,silk powder can be added as a reagent during the manufacture ofmicrospheres that are used as bulking agents.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in fecal incontinence devices and compositionsinclude talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin,and CTGF, as well as analogues and derivatives of the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or an analogue orderivative thereof.

Furthermore, the device may additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

The appropriate agents and their dosages can be further described belowin section (iii).

(ii) Prosthetic Anal Sphincters

Another approach to treating fecal incontinence involves implantation ofprostheses or devices, such as ablation devices, nerve stimulators,pumps, and stapling devices. Devices for treating fecal incontinence aredescribed in, e.g., U.S. Pat. Nos. 6,428,467; 6,013,023; 5,421,827;4,428,365; and 4,351,322 and in U.S. Published Patent ApplicationPublication No. 2002/0120219A1.

Devices for treating fecal incontinence which may be combined with oneor more fibrosis-inducing drugs according to the present inventioninclude a variety of commercially available products. For example, theSECCA system (Curon Medical) uses radio frequency ablation to tightenthe muscles of the anal sphincter. The ACTICON Neosphincter (made byActicon LLC and sold by American Medical Systems) is an implantableprosthesis that contains hand inflatable pump connected to an inflatablering in an artificial sphincter. The sacral nerve stimulator (Medtronic,Inc., Minneapolis, Minn.), is a device that addresses the neuropathythat results in fecal incontinence. The PROXIMATE stapling device fromEthicon EndoSurgery lifts up or repositions the mucosa or anal canaltissue to its original position.

In the present invention, fibrosis-inducing agents are combined withprosthetic anal sphincters to enhance scarring around the device and tore-enforce rectal anatomy to restore fecal continence. Numerouspolymeric and non-polymeric carrier systems described previously can beused to deliver one or more fibrosis-inducing agents to promote theformation of granulation tissue around the implanted device. The methodsfor incorporating fibrosis-inducing agents onto or into the fecalincontinence devices include: (a) directly affixing to the device afibrosing composition (e.g., by either a spraying process or dippingprocess as described above, with or without a carrier); (b) directlyincorporating into the device a fibrosing composition (e.g., by either aspraying process or dipping process as described above, with or withouta carrier); (c) by coating the device with a substance such as ahydrogel which can in turn absorb the fibrosing composition; (d) byinterweaving fibrosing composition coated thread (or the polymer itselfformed into a thread) into the device structure; (e) by inserting thedevice into a sleeve or mesh which is comprised of or coated with afibrosing composition; (f) constructing the device itself or a portionof the device with a fibrosing composition; or (g) by covalently bindingthe fibrosing agent directly to the device surface or to a linker (smallmolecule or polymer) that is coated or attached to the device surface.For these devices, the coating process can be performed in such a manneras to a) coat the exterior surfaces of the device, b) coat the interiorsurfaces of the device or c) coat all or parts of both external andinternal surface of the device.

In addition to coating the device with the fibrosing composition, thefibrosing agent can be mixed with the materials that are used to makethe device such that the fibrosing agent is incorporated into the finaldevice.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in fecal incontinence devices and compositionsinclude talc, silk, wool, chitosan, polylysine, fibronectin, bleomycin,and CTGF, as well as analogues and derivatives of the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or an analogue orderivative thereof.

Furthermore, the device may additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

Preferred specific agents and dosages of use for coating implantable,prosthetic devices used in the management of fecal incontinence aredescribed in section (iii) immediately below.

(iii) Fibrosis-Inducing Agents for Fecal Incontinence

As fecal incontinence devices are made in a variety of configurationsand sizes (including injectables and prosthetic implants), the exactdose administered can vary with device or implant size, surface area anddesign. However, certain principles can be applied in the application ofthis art. Drug dose can be calculated as a function of dose per unitvolume/area (of the total volume of bulking agent injected or of thesurface area of the portion of the prosthetic device being coated),total drug dose administered can be measured and appropriate surfaceconcentrations of active drug can be determined. Regardless of themethod of application of the fibrosis-inducing agent in the managementof fecal incontinence, the exemplary fibrosing agents, used alone or incombination, should be administered under the following dosingguidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered in a bulking agent injection, or coatedonto the surface of a fecal incontinence implant or device, should notexceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the totalamount of talc released should be in the range of 10 μg to 50 mg. Thedose per unit volume of the injectable bulking agent (i.e., the dosageof talc as a function of the volume of bulking agent injected) shouldfall within the range of 0.05 μg-10 μg per mm³. In another embodiment,talc should be applied to a fecal incontinence implant or device surfaceat a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. In oneembodiment, talc is released from a fecal incontinence bulking agent,implant or device such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example, in apreferred embodiment talc may be released in effective concentrationsfor a period ranging from 3-12 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives oftalc (as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as talc is administered at half the above parameters, a compoundhalf as potent as talc is administered at twice the above parameters,etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered in a bulking agent injection, or coatedonto the surface of a fecal incontinence implant or device, should notexceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the totalamount of silk released should be in the range of 10 μg to 50 mg. Thedose per unit volume of the injectable bulking agent (i.e., the dosageof silk as a function of the volume of bulking agent injected) shouldfall within the range of 0.05 μg-10 μg per mm³. In another embodiment,silk should be applied to a fecal incontinence device surface at a doseof 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific (polymericand non-polymeric) drug delivery vehicles and specific bulking agentsand prosthetic devices can release silk at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the fecal incontinence bulking agent, implant ordevice such that a minimum concentration of 0.01 nM to 1000 μM of silkis delivered to the tissue. In one embodiment, silk is released from afecal incontinence bulking agent, implant or device such that fibrosisin the tissue is promoted for a period ranging from several hours toseveral months. For example, in a preferred embodiment silk may bereleased in effective concentrations for a period ranging from 3-12months. It should be readily evident given the discussions providedherein that analogues and derivatives of silk (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as silk isadministered at half the above parameters, a compound half as potent assilk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered in a bulking agent injection, orcoated onto the surface of a fecal incontinence implant or device,should not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment,the total amount of chitosan released should be in the range of 10 μg to50 mg. The dose per unit volume of the injectable bulking agent (i.e.,the dosage of chitosan as a function of the volume of bulking agentinjected) should fall within the range of 0.05 μg-10 μg per mm³. Inanother embodiment, chitosan should be applied to a fecal incontinencedevice surface at a dose of 0.05 μg/mm²-10 μg/mm² of surface areacoated. As specific (polymeric and non-polymeric) drug delivery vehiclesand specific bulking agents and prosthetic devices can release chitosanat differing rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the fecalincontinence bulking agent, implant or device such that a minimumconcentration of 0.01 nM to 1000 μM of chitosan is delivered to thetissue. In one embodiment, chitosan is released from a fecalincontinence bulking injection, implant or device such that fibrosis inthe tissue is promoted for a period ranging from several hours toseveral months. For example, in a preferred embodiment chitosan may bereleased in effective concentrations for a period ranging from 3-12months. It should be readily evident given the discussions providedherein that analogues and derivatives of chitosan (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent aschitosan is administered at half the above parameters, a compound halfas potent as chitosan is administered at twice the above parameters,etc.).

Utilizing polylysine as a exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered in a bulking agent injection, orcoated onto the surface of a fecal incontinence implant or device,should not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment,the total amount of polylysine released should be in the range of 10 μgto 50 mg. The dose per unit volume of the injectable bulking agent(i.e., the dosage of polylysine as a function of the volume of bulkingagent injected) should fall within the range of 0.05 μg-10 μg per mm³.In another embodiment, polylysine should be applied to a fecalincontinence device surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific bulking agents and prosthetic devices canrelease polylysine at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe fecal incontinence bulking agent, device or implant such that aminimum concentration of 0.01 nM to 1000 μM of polylysine is deliveredto the tissue. In one embodiment, polylysine is released from a fecalincontinence bulking injection, implant or device such that fibrosis inthe tissue is promoted for a period ranging from several hours toseveral months. For example, in a preferred embodiment polylysine may bereleased in effective concentrations for a period ranging from 3-12months. It should be readily evident given the discussions providedherein that analogues and derivatives of polylysine (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent aspolylysine is administered at half the above parameters, a compound halfas potent as polylysine is administered at twice the above parameters,etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered from in a bulking agentinjection, or coated onto the surface of a fecal incontinence implant ordevice, should not exceed 100 mg (range of 1 μg to 100 mg). In oneembodiment, the total amount of fibronectin released should be in therange of 10 μg to 50 mg. The dose per unit volume of the injectablebulking agent (i.e., the dosage of fibronectin as a function of thevolume of bulking agent injected) should fall within the range of 0.05μg-10 μg per mm³. In another embodiment, fibronectin should be appliedto a fecal incontinence device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific bulking agents and prostheticdevices can release fibronectin at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the fecal incontinence bulking agent, implant or devicesuch that a minimum concentration of 0.01 nM to 1000 μM of fibronectinis delivered to the tissue. In one embodiment, fibronectin is releasedfrom a fecal incontinence bulking injection, implant or device such thatfibrosis in the tissue is promoted for a period ranging from severalhours to several months. For example, in a preferred embodimentfibronectin may be released in effective concentrations for a periodranging from 3-12 months. It should be readily evident given thediscussions provided herein that analogues and derivatives offibronectin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as fibronectin is administered at half theabove parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered in a bulking agent injection, orcoated onto the surface of a fecal incontinence implant or device,should not exceed 100 mg (range of 0.01 μg to 100 mg). In oneembodiment, the total amount of bleomycin released should be in therange of 0.10 μg to 50 mg. The dose per unit volume of the injectablebulking agent (i.e., the dosage of bleomycin as a function of the volumeof bulking agent injected) should fall within the range of 0.005 μg-10μg per mm³. In another embodiment, bleomycin should be applied to afecal incontinence device surface at a dose of 0.005 μg/mm²-10 μg/mm² ofsurface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific bulking agents and prosthetic devices canrelease bleomycin at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from thefecal incontinence bulking agent, implant or device such that a minimumconcentration of 0.001 nM to 1000 μM of bleomycin is delivered to thetissue. In one embodiment, bleomycin is released from a fecalincontinence bulking injection, implant or device such that fibrosis inthe tissue is promoted for a period ranging from several hours toseveral months. For example, in a preferred embodiment bleomycin may bereleased in effective concentrations for a period ranging from 3-12months. It should be readily evident given the discussions providedherein that analogues and derivatives of bleomycin (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asbleomycin is administered at half the above parameters, a compound halfas potent as bleomycin is administered at twice the above parameters,etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered in a bulking agent injection, or coatedonto the surface of a fecal incontinence implant or device, should notexceed 100 mg (range of 0.01 μg to 100 mg). In one embodiment, the totalamount of CTGF released should be in the range of 0.10 μg to 50 mg. Thedose per unit volume of the injectable bulking agent (i.e., the dosageof CTGF as a function of the volume of bulking agent injected) shouldfall within the range of 0.005 μg-10 μg per mm³. In another embodiment,CTGF should be applied to a fecal incontinence device surface at a doseof 0.005 μg/mm²-10 μg/mm² of surface area coated. As specific (polymericand non-polymeric) drug delivery vehicles and specific bulking agentsand prosthetic devices can release CTGF at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the fecal incontinence bulking agent, implant ordevice such that a minimum concentration of 0.001 nM to 1000 μM of CTGFis delivered to the tissue. In one embodiment, CTGF is released from afecal incontinence bulking injection, implant or device such thatfibrosis in the tissue is promoted for a period ranging from severalhours to several months. For example, in a preferred embodiment CTGF maybe released in effective concentrations for a period ranging from 3-12months. It should be readily evident given the discussions providedherein that analogues and derivatives of CTGF (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as CTGF isadministered at half the above parameters, a compound half as potent asCTGF is administered at twice the above parameters, etc.).

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or an analogue orderivative thereof. Inflammatory cytokines are to be used informulations at concentrations that range from 0.0001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the inflammatory cytokine is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.0001μg to 100 mg); preferred 0.001 μg to 50 mg. When used as a devicecoating, the dose is per unit area of 0.0001 μg-500 μg per mm²; with apreferred dose of 0.001 μg/mm²-200 μg/mm². Minimum concentration of10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to be maintained on thedevice surface.

Furthermore, the device may additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see, e.g., Example 16). The proliferative agents areto be used in formulations at concentrations that range from 0.1 ng/mlto 25 mg/ml depending on the specific clinical application, formulationtype (e.g., gel, liquid, solid, semi-solid), formulation chemistry,duration of required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

9. Gastroesophageal Reflux Disease (GERD)

The present invention provides compositions and devices for use in themanagement of gastroesophageal reflux disease (GERD). GERD occurs whenthe lower esophageal sphincter (the muscle between the stomach and theesophagus) is unable to prevent the contents of the stomach fromrefluxing back into the esophagus. Gastric acid and enzymes are quitecorrosive to the epithelial lining of the esophagus and can causeerosions, ulceration, scarring and narrowing of the esophagus.Repetitive reflux into the esophagus can result in irreversible injuryand also predisposes the patient to the development of esophagealcancer.

(i) GERD Bulking Agents

One approach to treating GERD involves lower esophageal sphincteraugmentation. One method for augmenting the lower esophageal sphincterinvolves delivery (e.g., injection) of a bulking agent (e.g., a collagenbulking agent) into the vicinity of the lower esophageal sphincter (LES)(e.g., into the perimuscular space of the LES) to restore the structureof the tissue and reduce backflow into the esophagus. Another approachinvolves implantation of bulking devices or devices that deliverexpandable polymeric compositions (e.g., hydrogel prostheses).

As mentioned above, GERD may be treated by injecting a bulking agentclose to the lower esophageal sphincter to reinforce closure of the LES.Bulking agents which may be combined with one or more fibrosis-inducingagents according to the present invention, include numerous commerciallyavailable products. For example, injectable microspheres from ArtesMedical, ENTERYX and CONTIGEN (purified bovine dermal glutaraldehydecrosslinked collagen dispersed in phosphate buffered physiologic salineat 35 mg/ml available through C.R. Bard, Billerica, Mass.) are widelyused bulking agents. Other collagen based injectable products, includingthose derived from non-bovine, human, or recombinant sources can also beutilized in this embodiment. Additional representative examples ofcommercially available bulking agents that can be loaded with afibrosis-inducing agent and used to treat GERD include COAPATITE,CYMETRA, DEFLUX, DURASPHERE, engineered collagen fibrils fromOrganogenesis, HYLAGEL URO, MACROPLASTIQUE, microspheres (e.g., acrylicbeads, such as those available from Biosphere Medical), LES bulkingagents containing silk and elastin proteins (such as those availablefrom Protein Polymer Technologies), UROVIVE, and URYX bulking agent.Another device suitable for use with a fibrosis-inducing agent in themanagement of GERD includes the GATEKEEPER Reflux Repair System made byMedtronic, Inc. (Minneapolis, Minn.). Other manufacturers of carrierssuitable for delivering a fibrosis-inducing agent for use in GERDbulking compositions include C.R. Bard, Collagenesis, American MedicalSystems, Mentor, Uromed, BSX, Johnson & Johnson (Ethicon, Inc.), CookInc., W.L. Gore & Associates, and SURx. Examples of implantable loweresophageal bulking devices are also described in WO 00/12027A1 and U.S.Pat. No. 6,401,718.

Regardless of their composition, bulking agents are designed to providephysical support for the lower esophageal sphincter and prevent thereflux of gastric contents into the esophagus. Unfortunately,symptomatic relief is often only temporary for most patients and theprocedure must often be repeated. Biodegradable injectable materials(such as collagen, hyaluronic acid and others described above) areabsorbed by the body over time and lose their structuralintegrity—necessitating replacement of the material via repeatinjection. Non degradable materials (such as acrylics, hydroxyapatite,polymeric beads, and others described above) do not regenerate thenormal structural anatomy or biomechanics of the tissues surrounding thelower esophageal sphincter. The addition of a fibrosis-inducing agent toa bulking agent solves several of these problems. The fibrosis-inducingagent encourages the formation of the body's own fibrous tissue(including collagen) around the lower esophageal sphincter. This resultsin the formation of continuously sustainable connective tissue whichsupports the LES in a manner more closely approximating normalgastroesophageal anatomy and biomechanics. The result is a treatmentthat lasts longer, provides better symptomatic relief and requires fewerre-interventions.

In one aspect, the present invention provides injectable compositions(bulking agents) for use in treating GERD. Specifically, thefibrosis-inducing agent can be produced with or without a carrier (suchas collagen, hyaluronic acid, and/or another biocompatible polymer)which is then injected in and around the anal sphincter to providesupport and continence. In one embodiment, fibrosis-inducing agents canbe incorporated directly into the formulation to produce a suspension ora solution (e.g., silk powder, bleomycin) or it can be incorporated intoa secondary carrier (e.g., micelles, liposomes, microspheres,microparticles, nanospheres, microparticulates, emulsions and/ormicroemulsions) that is then incorporated into the bulking composition.In another embodiment, the fibrosis-inducing agent can beelectrostatically or covalently bound to one or more of the polymericcomponents of the in situ forming composition. Injection of the bulkingagent (many commercial examples of which were described above)containing the fibrosing agent into the perimuscular space (alone or incombination with a polymeric carrier) can enhance scarring and supportto the lower esophageal sphincter and may result in endogenous collagenproduction.

In another embodiment, the fibrosis-inducing agent can be incorporatedinto the bulking agent during the manufacture of the agent. For example,silk powder can be added as a reagent during the manufacture ofmicrospheres that are used as bulking agents.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in GERD bulking agents include talc, silk,wool, chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well asanalogues and derivatives of the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or an analogue orderivative thereof.

Furthermore, the device may additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

The appropriate agents and their dosages can be further described belowin section (iii).

(ii) Devices Used in GERD

A variety of implantable devices and methods have been described for usein treating GERD. Representative treatment methods include, for example,suture-based treatments and the use of energy based devices. Suturebased treatments for GERD are described in, e.g., U.S. Pat. No.6,494,888, U.S. Patent Application Publication No. 2002/0138075A1describes a sphincter electropotential mapping device. U.S. Pat. No.6,321,121 describes a lower esophageal sphincter tightening device.Other devices for treating GERD are described in, e.g., U.S. Pat. Nos.6,092,528, 6,159,146; 6,113,609; 5,571,116; 6,432,040; and 6,264,700;U.S. Patent Application Publication No. 2003/0199731A1, and PCTPublication Nos. WO 99/44520A1 and WO 01/24721A1.

Suture-based treatments for treating GERD may be combined with one ormore fibrosis-inducing agents according to the present invention.Several commercially available products can be combined withfibrosis-inducing agents including: (a) the ENDOCINCH AND ENDOCINCH IISuturing System (C.R. Bard) which uses a procedure that createsplications, or pleats, at the lower esophageal sphincter; (b) theENDOSCOPIC Suturing Device (ESD) (Wilson-Cook, Winston-Salem, N.C.)which is composed of the Flexible SEW-RIGHT device, the Flexible TI-KNOTdevice, and an external accessory channel; (c) the PLICATOR SYSTEM (NDOSurgical, Mansfield Mass.) which allows physicians to create afull-thickness plication at the gastroesophageal junction, permittingserosa-to-serosa healing and restructuring healing and restructuring ofthe LES; and (d) the HISWIZ (Olympus, Inc.) suture-based device.

Another approach to treating GERD is through the use of energy-baseddevices. Energy delivery devices for treating esophageal sphincters aredescribed, e.g., in U.S. Pat. Nos. 6,613,047 and 6,009,877. Tissueablation devices are described e.g., in U.S. Pat. Nos. 6,112,123 and6,258,087. Energy-based devices for treating GERD which may be combinedwith one or more fibrosis-inducing agents according to the presentinvention include several commercially available products, such as theSTRETTA system (Curon Medical) radio frequency (RF) ablation device.

In the present invention, fibrosis-inducing agents are combined withsuture-based and energy-based treatments of GERD to enhance scarringaround the device, re-enforce LES anatomy and prevent gastroesophagealreflux. Numerous polymeric and non-polymeric carrier systems describedpreviously can be used to deliver one or more fibrosis-inducing agentsand promote the formation of granulation tissue around the implanteddevice. The methods for incorporating fibrosis-inducing agents onto orinto the implanted GERD devices include: (a) directly affixing to theimplanted suture a fibrosing composition (e.g., by either a sprayingprocess or dipping process as described previously, with or without acarrier); (b) directly incorporating into the polymers which compose thesutures themselves a fibrosing composition; (c) by coating the sutureswith a substance such as a hydrogel which can in turn absorb thefibrosing composition, (d) by interweaving fibrosing composition coatedthread (or the polymer itself formed into a thread) into the suturingmaterial; (e) by constructing the suture itself or a portion of thesuture with a fibrosing composition (particularly silk); or (f) bycovalently binding the fibrosing agent directly to the surface of thesuture or the surface of the gastric mucosa (or utilizing a linker smallmolecule or polymer to accomplish this); (g) by applying (e.g.,infusing, spraying, injecting) the fibrosis-inducing agent into the LESor the gastric mucosal (or serosal) surface, either alone or in apolymeric carrier (e.g., collagen, COSTASIS, materials made from 4-armedthiol PEG (10K), a 4-armed NHS PEG(10K) and methylated collagen such asdescribed above, fibrin, PMMA, CORTOSS, cyanoacrylate, hyaluronic acid,EVA, PLA and other polymers described previously), to induce scarring inthe sphincter or across the plication created by the suture device;and/or (h) applying (e.g., infusing, spraying, injecting) afibrosis-inducing agent, with or without a polymeric carrier, into thetissues into which energy is being applied (to enhance scarring).

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in the treatment of GERD include talc, silk,wool, chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well asanalogues and derivatives of the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or an analogue orderivative thereof.

Furthermore, the device may additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

Preferred specific agents and dosages of use for coating implantable,prosthetic devices used in the management of GERD are described insection (iii) immediately below.

(iii) Fibrosis-Inducing Agents for GERD

As GERD devices are made in a variety of configurations and sizes(including injectables and implants), the exact dosage administered canvary with the amount injected or the size, surface area and design ofthe implant material. However, certain principles can be applied in theapplication of this art. Drug dose can be calculated as a function ofdose per unit volume/area (of the total volume of bulking agent injectedor of the surface area of the portion of the implant being coated),total drug dose administered can be measured and appropriate surfaceconcentrations of active drug can be determined. Regardless of themethod of application of the fibrosis-inducing agent in the managementof GERD, the exemplary fibrosing agents, used alone or in combination,should be administered under the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered in bulking agent injection, or coatedonto the surface of a GERD implant or device, should not exceed 100 mg(range of 1 μg to 100 mg). In one embodiment, the total amount of talcreleased should be in the range of 10 μg to 50 mg. The dose per unitvolume of the injectable bulking agent (i.e., the dosage of talc as afunction of the volume of bulking agent injected) should fall within therange of 0.05 μg-10 μg per mm³. In another embodiment, talc should beapplied to a GERD implant or device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. In one embodiment, talc is released froma GERD bulking agent, device or implant such that fibrosis in the tissueis promoted for a period ranging from several hours to several months.For example, in a preferred embodiment talc may be released in effectiveconcentrations for a period ranging from 3-12 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of talc (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as talc is administered at half the aboveparameters, a compound half as potent as talc is administered at twicethe above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered in bulking agent injection, or coatedonto the surface of a GERD implant or device, should not exceed 100 mg(range of 1 μg to 100 mg). In one embodiment, the total amount of silkreleased should be in the range of 10 μg to 50 mg. The dose per unitvolume of the injectable bulking agent (i.e., the dosage of silk as afunction of the volume of bulking agent injected) should fall within therange of 0.05 μg-10 μg per mm³. In another embodiment, silk should beapplied to a GERD implant or device surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific bulking agents, implants and devicescan release silk at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from theGERD bulking agent, implant or device such that a minimum concentrationof 0.01 nM to 1000 μM of silk is delivered to the tissue. In oneembodiment, silk is released from a GERD bulking injection, implant ordevice such that fibrosis in the tissue is promoted for a period rangingfrom several hours to several months. For example, in a preferredembodiment silk may be released in effective concentrations for a periodranging from 3-12 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of silk (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent assilk is administered at half the above parameters, a compound half aspotent as silk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered in bulking agent injection, orcoated onto the surface of a GERD implant or device, should not exceed100 mg (range of 1 μg to 100 mg). In one embodiment, the total amount ofchitosan released should be in the range of 10 μg to 50 mg. The dose perunit volume of the injectable bulking agent (i.e., the dosage ofchitosan as a function of the volume of bulking agent injected) shouldfall within the range of 0.05 μg-10 μg per mm³. In another embodiment,chitosan should be applied to a GERD implant or device surface at a doseof 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific (polymericand non-polymeric) drug delivery vehicles and specific bulking agents,implants and devices can release chitosan at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the GERD bulking agent, implant or device suchthat a minimum concentration of 0.01 nM to 1000 μM of chitosan isdelivered to the tissue. In one embodiment, chitosan is released from ofa GERD bulking agent, implant or device such that fibrosis in the tissueis promoted for a period ranging from several hours to several months.For example, in a preferred embodiment chitosan may be released ineffective concentrations for a period ranging from 3-12 months. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of chitosan (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as chitosan isadministered at half the above parameters, a compound half as potent aschitosan is administered at twice the above parameters, etc.).

Utilizing polylysine as a exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered in bulking agent injection, orcoated onto the surface of a GERD implant or device, should not exceed100 mg (range of 1 μg to 100 mg). In one embodiment, the total amount ofpolylysine released should be in the range of 10 μg to 50 mg. The doseper unit volume of the injectable bulking agent (i.e., the dosage ofpolylysine as a function of the volume of bulking agent injected) shouldfall within the range of 0.05 μg-10 μg per mm³. In another embodiment,polylysine should be applied to a GERD implant or device surface at adose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificbulking agents, implants and devices can release polylysine at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the GERD bulking agent, device orimplant such that a minimum concentration of 0.01 nM to 1000 μM ofpolylysine is delivered to the tissue. In one embodiment, polylysine isreleased from a GERD bulking agent, implant or device such that fibrosisin the tissue is promoted for a period ranging from several hours toseveral months. For example, in a preferred embodiment polylysine may bereleased in effective concentrations for a period ranging from 3-12months. It should be readily evident given the discussions providedherein that analogues and derivatives of polylysine (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent aspolylysine is administered at half the above parameters, a compound halfas potent as polylysine is administered at twice the above parameters,etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered in bulking agentinjection, or coated onto the surface of a GERD implant or device,should not exceed 100 mg (range of 1 μg to 100 mg). In one embodiment,the total amount of fibronectin released should be in the range of 10 μgto 50 mg. The dose per unit volume of the injectable bulking agent(i.e., the dosage of fibronectin as a function of the volume of bulkingagent injected) should fall within the range of 0.05 μg-10 μg per mm³.In another embodiment, fibronectin should be applied to a GERD implantor device surface at a dose of 0.05 μg/mm²-10 μg/mm² of surface areacoated. As specific (polymeric and non-polymeric) drug delivery vehiclesand specific bulking agents, implants and devices can releasefibronectin at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from the GERDbulking agent, implant or device such that a minimum concentration of0.01 nM to 1000 μM of fibronectin is delivered to the tissue. In oneembodiment, fibronectin is released from a GERD bulking agent, implantor device such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, in apreferred embodiment fibronectin may be released in effectiveconcentrations for a period ranging from 3-12 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of fibronectin (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as fibronectin is administered at halfthe above parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered in bulking agent injection, orcoated onto the surface of a GERD implant or device, should not exceed100 mg (range of 0.01 μg to 100 mg). In one embodiment, the total amountof bleomycin released should be in the range of 0.10 μg to 50 mg. Thedose per unit volume of the injectable bulking agent (i.e., the dosageof bleomycin as a function of the volume of bulking agent injected)should fall within the range of 0.005 μg-10 μg per mm³. In anotherembodiment, bleomycin should be applied to a GERD implant or devicesurface at a dose of 0.005 μg/mm²-10 μg/mm² of surface area coated. Asspecific (polymeric and non-polymeric) drug delivery vehicles andspecific bulking agents, implants and devices can release bleomycin atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the GERD bulkingagent, implant or device such that a minimum concentration of 0.001 nMto 1000 μM of bleomycin is delivered to the tissue. In one embodiment,bleomycin is released from a GERD bulking agent, implant or device suchthat fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, in a preferred embodimentbleomycin may be released in effective concentrations for a periodranging from 3-12 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of bleomycin(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as bleomycin is administered at half the above parameters, acompound half as potent as bleomycin is administered at twice the aboveparameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered in bulking agent injection, or coatedonto the surface of a GERD implant or device, should not exceed 100 mg(range of 0.01 μg to 100 mg). In one embodiment, the total amount ofCTGF released should be in the range of 0.10 μg to 50 mg. The dose perunit volume of the injectable bulking agent (i.e., the dosage of CTGF asa function of the volume of bulking agent injected) should fall withinthe range of 0.005 μg-10 μg per mm³. In another embodiment, CTGF shouldbe applied to a GERD implant or device surface at a dose of 0.005μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific bulking agents,implants and devices can release CTGF at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the GERD bulking agent, implant or device suchthat a minimum concentration of 0.001 nM to 1000 μM of CTGF is deliveredto the tissue. In one embodiment, CTGF is released from a GERD bulkingagent, implant or device such that fibrosis in the tissue is promotedfor a period ranging from several hours to several months. For example,in a preferred embodiment CTGF may be released in effectiveconcentrations for a period ranging from 3-12 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of CTGF (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as CTGF is administered at half the aboveparameters, a compound half as potent as CTGF is administered at twicethe above parameters, etc.).

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or an analogue orderivative thereof.

Inflammatory cytokines are to be used in formulations at concentrationsthat range from 0.0001 μg/ml to approximately 20 mg/ml depending on thespecific clinical application, formulation type (e.g., gel, liquid,solid, semi-solid), formulation chemistry, duration of requiredapplication, type of medical device interface and formulation volume andor surface area coverage required. Preferably, the inflammatory cytokineis released in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see, e.g., Example 16). The proliferative agents areto be used in formulations at concentrations that range from 0.1 ng/mlto 25 mg/ml depending on the specific clinical application, formulationtype (e.g., gel, liquid, solid, semi-solid), formulation chemistry,duration of required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

10. Morbid Obesity

The present invention provides fibrosis-inducing compositions anddevices for use in the management of morbid obesity. Morbid obesity(people who are more than 50% above their ideal body weight) is asignificant public health problem that affects a significant (andgrowing) percentage of the population in the Western world. Morbidobesity predisposes the patient to a variety of significant healthproblems including heart disease, diabetes, stroke, kidney disease,joint disease and a shortened lifespan. Numerous interventionalprocedures have been developed to address the problem includingstrategies designed to surgically decrease the size of the stomach. Thisphysically limits the amount of food that can be consumed, provides asense of satiety and ultimately leads to weight loss due to decreasedfood and caloric intake. The present invention describes the addition offibrosis-inducing agents combined with gastric restriction devices toimprove the efficacy of the procedure.

An example of a gastric restriction device is a laparoscopicallyinstalled inflatable cuff (referred to as a lap-band) that is placedaround the top of the stomach just below the lower esophageal sphincter(LES). For a further description, see, for example, U.S. Pat. Nos.5,601,604; 5,226,429; and 5,074,868. Additional examples of restrictiondevices used for the management of obesity are described in, e.g., U.S.Pat. Nos. 6,067,991; 6,454,699; 6,453,907; 6,450,946; 6,210,347; and6,067,991. Other minimally invasive devices include, but are not limitedto, space occupying devices, suture-based endoluminal devices forpartitioning the stomach, electrostimulation devices (e.g., neural andnon-neural), and radio frequency antralplasty devices. Space occupyingdevices (e.g., intragastric balloons) are described, for example, inU.S. Pat. Nos. 5,259,399; 4,485,805; 5,129,915; 5,259,399; and6,454,785. Electrostimulation devices for the treatment of obesity aredescribed in, e.g., U.S. Pat. Nos. 6,615,084; 6,129,685; 5,782,798,6,535,764; and 6,606,523.

In one aspect, restriction devices can be combined withfibrosis-inducing agents for the treatment of obesity. Specifically,several commercially available restriction products are suitable for thepractice of this invention including: the LAP-BAND Adjustable GastricBanding System (made by Inamed) which involves a small ring ofinflatable silicone that can be inflated or deflated from an attachedtubing connected to a subcutaneous port), the SWEDISH ADJUSTABLE GASTRICBAND (by Ethicon-Endosurgery) is a low pressure inflatable devicereinforced with a DACRON net that is fitted around the uppermost part ofthe stomach laparoscopically and can be adjusted after placement byinjecting or removing fluid).

Also in the present invention, numerous commercially available minimallyinvasive devices for treating obesity can be combined with one or morefibrosis-inducing agents. Specifically, space occupying minimallyinvasive devices suitable for use in the practice of this inventioninclude: the BARIATRIC INTRAGASTRIC BALLOON (by Inamed) is a sphericalsilicon implant placed in the stomach and expanded with saline to400-800 ml that can be left in place for 3-6 months), an intragastricballoon available from Satiety, Inc., the BOWTIE space occupying devicemade from a continuous ribbon of polyester (Wilson-Cook, Inc.), and asuture-based endoluminal device for partitioning the stomach, such asthe EAGLE CLAW (Olympus America).

The addition of a fibrosis-inducing agent to a gastric band device or aspace occupying device can enhance efficacy and longevity of theprocedure in several ways. For example, inducing fibrous tissue aroundthe implant can secure the implant in place allowing it to maintain theproper anatomical position in the stomach. Also, fibrous tissue can forma permanent “band” in the stomach that results in sustained, host tissueshrinkage of the stomach. As the scar matures it can also contract,further reducing the size of the stomach and improving the efficacy ofthe procedure.

Numerous polymeric and non-polymeric carrier systems described in detailpreviously can be used in the practice of this invention. Thesecompositions can further comprise one or more fibrosis-inducing agentsto promote the formation of granulation tissue. The methods forincorporating fibrosing compositions onto or into gastric restriction orspace occupying obesity devices include: (a) directly affixing to thedevice a fibrosing composition (e.g., by either a spraying process ordipping process as described above, with or without a carrier); (b)directly incorporating into the device a fibrosing composition (e.g., byeither a spraying process or dipping process as described above, with orwithout a carrier); (c) by coating the device with a substance such as ahydrogel which can in turn absorb the fibrosing composition; (d) byinterweaving fibrosing composition coated thread (or the polymer itselfformed into a thread) into the device structure; (e) by inserting thedevice into a sleeve or mesh which is comprised of or coated with afibrosing composition; (f) constructing the device itself or a portionof the device with a fibrosing composition; and/or (g) by covalentlybinding the fibrosing agent directly to the device surface or to alinker (small molecule or polymer) that is coated or attached to thedevice surface. For these devices, the coating process can be performedin such a manner as to a) coat the exterior surfaces of the device, b)coat the interior surfaces of the device or c) coat all or parts of bothexternal and internal surface of the device. In addition to coating thedevice with the fibrosing composition, the fibrosing agent can be mixedwith the materials that are used to make the device such that thefibrosing agent is incorporated into the final device.

In one embodiment fibrosis-inducing agents can be incorporated directlyinto the formulation to produce a suspension or a solution (e.g., silkpowder, bleomycin) or it can be incorporated into a secondary carrier(e.g., micelles, liposomes, microspheres, microparticles, nanospheres,microparticulates, emulsions and/or microemulsions) that is thenincorporated into the gastric restriction device or space occupyingdevice. In another embodiment, the fibrosis-inducing agent can beelectrostatically or covalently bound to one or more of the polymericcomponents of the in situ forming composition.

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in obesity devices and compositions includetalc, silk, wool, chitosan, polylysine, fibronectin, bleomycin, andCTGF, as well as analogues and derivatives of the aforementioned.

As obesity devices are made in a variety of configurations and sizes,the exact dose administered can vary with device size, surface area anddesign. However, certain principles can be applied in the application ofthis art. Drug dose can be calculated as a function of dose per unitarea (of the portion of the device being coated), total drug doseadministered can be measured and appropriate surface concentrations ofactive drug can be determined. Regardless of the method of applicationof the drug to the obesity device, the exemplary fibrosing agents, usedalone or in combination, should be administered under the followingdosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered from a obesity device, or coated ontothe surface of an obesity device, should not exceed 100 mg (range of 1μg to 100 mg). In one embodiment, the total amount of talc released fromthe prosthesis should be in the range of 10 μg to 50 mg. The dose perunit area of the device (i.e., the dosage of talc as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, talc should beapplied to an obesity device surface at a dose of 0.05 μg/mm²-10 μg/mm²of surface area coated. In one embodiment, talc is released from thesurface of an obesity device such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, talc may be released in effective concentrations for a periodranging from 1-9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of talc (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent astalc is administered at half the above parameters, a compound half aspotent as talc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered from a obesity device, or coated ontothe surface of an obesity device, should not exceed 100 mg (range of 1μg to 100 mg). In one embodiment, the total amount of silk released fromthe prosthesis should be in the range of 10 μg to 50 mg. The dose perunit area of the device (i.e., the dosage of silk as a function of thesurface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, silk should beapplied to an obesity device surface at a dose of 0.05 μg/mm²-10 μg/mm²of surface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific medical devices can release silk atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the obesity devicesuch that a minimum concentration of 0.01 nM to 1000 μM of silk isdelivered to the tissue. In one embodiment, silk is released from thesurface of an obesity device such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, silk may be released in effective concentrations for a periodranging from 1-9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of silk (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent assilk is administered at half the above parameters, a compound half aspotent as silk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered from an obesity device, or coatedonto the surface of an obesity device, should not exceed 100 mg (rangeof 1 μg to 100 mg). In one embodiment, the total amount of chitosanreleased from the prosthesis should be in the range of 10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of chitosan as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.05μg-10 μg per mm² of surface area coated. In another embodiment, chitosanshould be applied to an obesity device surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease chitosan at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from theobesity device such that a minimum concentration of 0.01 nM to 1000 μMof chitosan is delivered to the tissue. In one embodiment, chitosan isreleased from the surface of an obesity device such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, chitosan may be released in effectiveconcentrations for a period ranging from 1-9 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of chitosan (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as chitosan is administered at halfthe above parameters, a compound half as potent as chitosan isadministered at twice the above parameters, etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered from an obesity device, or coatedonto the surface of an obesity device, should not exceed 100 mg (rangeof 1 μg to 100 mg). In one embodiment, the total amount of polylysinereleased from the prosthesis should be in the range of 10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of polylysine asa function of the surface area of the portion of the device to whichdrug is applied and/or incorporated) should fall within the range of0.05 μg-10 μg per mm² of surface area coated. In another embodiment,polylysine should be applied to an obesity device surface at a dose of0.05 μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical devices canrelease polylysine at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe obesity device such that a minimum concentration of 0.01 nM to 1000μM of polylysine is delivered to the tissue. In one embodiment,polylysine is released from the surface of an obesity device such thatfibrosis in the tissue is promoted for a period ranging from severalhours to several months. For example, polylysine may be released ineffective concentrations for a period ranging from 1-9 months. It shouldbe readily evident given the discussions provided herein that analoguesand derivatives of polylysine (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as polylysine is administered at halfthe above parameters, a compound half as potent as polylysine isadministered at twice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered from an obesity device,or coated onto the surface of an obesity device, should not exceed 100mg (range of 1 μg to 100 mg). In one embodiment, the total amount offibronectin released from the prosthesis should be in the range of 10 μgto 50 mg. The dose per unit area of the device (i.e., the dosage offibronectin as a function of the surface area of the portion of thedevice to which drug is applied and/or incorporated) should fall withinthe range of 0.05 μg-10 μg per mm² of surface area coated. In anotherembodiment, fibronectin should be applied to an obesity device surfaceat a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificmedical devices can release fibronectin at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the obesity device such that a minimumconcentration of 0.01 nM to 1000 μM of fibronectin is delivered to thetissue. In one embodiment, fibronectin is released from the surface ofan obesity device such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example,fibronectin may be released in effective concentrations for a periodranging from 1-9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives offibronectin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as fibronectin is administered at half theabove parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered from an obesity device, or coatedonto the surface of an obesity device, should not exceed 100 mg (rangeof 0.01 μg to 100 mg). In one embodiment, the total amount of bleomycinreleased from the prosthesis should be in the range of 0.10 μg to 50 mg.The dose per unit area of the device (i.e., the dosage of bleomycin as afunction of the surface area of the portion of the device to which drugis applied and/or incorporated) should fall within the range of 0.005μg-10 μg per mm² of surface area coated. In another embodiment,bleomycin should be applied to an obesity device surface at a dose of0.005 μg/mm²-10 μg/mm² of surface area coated. As specific (polymericand non-polymeric) drug delivery vehicles and specific medical devicescan release bleomycin at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe obesity device such that a minimum concentration of 0.001 nM to 1000μM of bleomycin is delivered to the tissue. In one embodiment, bleomycinis released from the surface of an obesity device such that fibrosis inthe tissue is promoted for a period ranging from several hours toseveral months. For example, bleomycin may be released in effectiveconcentrations for a period ranging from 1-9 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of bleomycin (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as bleomycin is administered at halfthe above parameters, a compound half as potent as bleomycin isadministered at twice the above parameters, etc.).

Utilizing CTGF as a exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered from an obesity device, or coated ontothe surface of an obesity device, should not exceed 100 mg (range of0.01 μg to 100 mg). In one embodiment, the total amount of CTGF releasedfrom the prosthesis should be in the range of 0.10 μg to 50 mg. The doseper unit area of the device (i.e., the dosage of CTGF as a function ofthe surface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.005 μg-10 μg permm² of surface area coated. In another embodiment, CTGF should beapplied to an obesity device surface at a dose of 0.005 μg/mm²-10 μg/mm²of surface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific medical devices can release CTGF atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the obesity devicesuch that a minimum concentration of 0.001 nM to 1000 μM of CTGF isdelivered to the tissue. In one embodiment, CTGF is released from thesurface of an obesity device such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, CTGF may be released in effective concentrations for a periodranging from 1-9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of CTGF (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asCTGF is administered at half the above parameters, a compound half aspotent as CTGF is administered at twice the above parameters, etc.).

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone or an analogue orderivative thereof). Inflammatory cytokines are to be used informulations at concentrations that range from 0.0001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the inflammatory cytokine is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.0001μg to 100 mg); preferred 0.001 μg to 50 mg. When used as a devicecoating, the dose is per unit area of 0.0001 μg-500 μg per mm²; with apreferred dose of 0.001 μg/mm²-200 μg/mm². Minimum concentration of10⁻¹¹-10⁴ g/ml of inflammatory cytokine is to be maintained on thedevice surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see, e.g., Example 16). The proliferative agents areto be used in formulations at concentrations that range from 0.1 ng/mlto 25 mg/ml depending on the specific clinical application, formulationtype (e.g., gel, liquid, solid, semi-solid), formulation chemistry,duration of required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

11. Soft Palate Implants

The present invention provides for the combination of afibrosis-inducing agent and soft palate implant devices for thetreatment of snoring and sleep apnea (also referred to as obstructivesleep apnea (OSA)). Sleep apnea refers to the inability to maintainnormal respiration and oxygenation while sleeping. Obstructive sleepapnea is characterized by frequent periods of airway occlusion duringsleep, with concomitant obstruction of inspiratory airflow, drop inblood oxygen and interruption of sleep when the patient awakes to usevoluntary muscle contraction to open the airway and take a few deepbreaths. Also of consideration is the impact that loud snoring (oftenreaching decibel levels equated with the take-off of an airplane) has onthe sleeping patterns and lifestyle of the partner of a patient withobstructive sleep apnea. Sleep apnea can arise from a mechanicalobstruction of an airway and can involve painful and/or insufficientbreathing, an abnormal heartbeat, and hypertension. The mechanicallocations and structural causes of obstruction are multiple. The mostfrequent mechanisms include settling of the tongue, uvula, soft palateor other tissues against the airway during the negative pressureassociated with inspiration. This may be related to adipose tissueaccumulation, lack of muscle tone or inadequate central respiratorydrive to the tongue and/or other accessory respiratory muscles aroundthe oropharyngeal airway. Treatment of sleep apnea includes surgicalprocedures (such as uvulectomy or removal of the uvula, surgical removalof soft tissue in the airway, or stiffening the palate through theremoval of tissue and the induction of scarring), behavioral control ofsleep posture, positive airway pressure applied via a face mask, and theuse of implantable sleep apnea devices (such as soft palate implants).

The present invention describes soft palate implants combined with afibrosis-inducing agent to enhance scarring around the implant andimprove efficacy of the device. Injectable compositions, with or withoutthe addition of a fibrosis-inducing agent, described in section (i), maybe injected into the submucosa of the palate to provide physical supportof the tissue. The combination of a fibrosis-inducing agent with softpalate prosthesis (or solid implant) is described in section (ii).

Regardless of their design, soft palate injectables and implants aredesigned to provide physical support for the uvula and prevent the softpalate from obstructing the airway during sleep. Unfortunately, thesymptomatic relief can be only temporary for many patients as support ofthe soft palate is incomplete or there is insufficient scarring aroundthe implant to create a permanent result. The addition of afibrosis-inducing agent to a palatal implant can increase the amount ofscar tissue surrounding the implant and improve the long term outcome ofthe procedure. The fibrosis-inducing agent encourages the formation ofthe body's own fibrous tissue (including collagen) around the softpalate implant to provide support; the natural contracture of the scarwith time further elevates the uvula and increases the size of theairway. This results in the formation of continuously sustainableconnective tissue which supports the uvula in a manner more closelyapproximating nasopharyngeal anatomy and biomechanics. The result is atreatment that lasts longer, provides better symptomatic relief andrequires fewer re-interventions.

(i) Injectable Fibrosis-Inducing Palatal Implants

The present invention describes degradable and non-degradable injectablebiomaterials and implants, alone or combined with a fibrosis-inducingagent, growth factor or sclerosing agent, for injection into the softpalate for the treatment of sleep apnea. Typically, a needle or catheteris advanced into the submucosa of the soft palate and the injectableimplant is deployed. The addition of a fibrosis-inducing agent,sclerosing agent and/or growth factor to the materials injected into thesoft palate produces a permanent scar that supports the uvula and opensthe airway.

A variety of injectable polymer-based products have been developed thatare suitable for the practice of this invention and can be used alone orin combination with a fibrosis-inducing agent. Examples of productssuitable for injection into the soft palate, alone or with afibrosis-inducing agent, include: TRUFILL n-butyl cyanoacrylate (n-BCA)Liquid Embolic System (Cordis, a division of Johnson and Johnson, Miami,Fla.); EMBOSPHERE and EMBOGOLD Microspheres; ONYX Liquid Embolic System;BEAD BLOCK; PVA particles from Cook, Inc. and Angiodynamics, Inc.; andin situ forming materials from Biocure, Angiotech Pharmaceuticals, Inc.,3M Company and Neomend.

Several other injectable compositions are suitable for injection intothe soft palate for the treatment of sleep apnea. All involve thedeployment of a biomaterial into the tissues of the soft palate, with orwithout the addition of a fibrosis-inducing agent, sclerosing agent,and/or suitable growth factor(s). The following compositions can bedelivered via specialized delivery catheters, a needle or otherapplicator, or a surgically placed access device under direct orendoscopic vision. Examples of appropriate injectable materials whichmay be injected into the soft palate include: (a) fluids, suspensions,emulsions, microemulsions, microspheres, pastes, gels,microparticulates, sprays, aerosols, solid implants and otherformulations which release a biologically active agent(s); (b)microparticulate silk and/or silk strands (linear, branched, and/orcoiled) either alone, or loaded with an additional fibrosis-inducingagent, sclerosing agent, and/or growth factor injected into the softpalate; (c) injectable collagen-containing formulations such as COSTASISor materials prepared from a 4-armed thiol PEG (10K), a 4-armed NHSPEG(10K) and methylated collagen such as described above, either alone,or loaded with a fibrosis-inducing agent, sclerosing agent, and/orgrowth factor; (d) injectable PEG-containing formulations such asCOSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, either alone, or loaded with afibrosis-inducing agent, sclerosing agent, and/or growth factor; (e)fibrinogen-containing formulations such as FLOSEAL or TISSEAL, eitheralone, or loaded with a fibrosis-inducing agent, sclerosing agent,and/or growth factor; (f) hyaluronic acid-containing formulations suchas RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, eitheralone, or loaded with a fibrosis-inducing agent, sclerosing agent,and/or growth factor; (g) polymeric gels for surgical implantation suchas REPEL or FLOWGEL either alone, or loaded with a fibrosis-inducingagent, sclerosing agent, and/or growth factor; (h) orthopedic “cements”such as OSTEOBOND, LVC, SIMPLEX P, PALACOS, CORTOSS, and ENDURANCE,either alone, or loaded with a fibrosis-inducing agent, sclerosingagent, and/or growth factor; (i) surgical adhesives containingcyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND,HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT, eitheralone, or loaded with a fibrosis-inducing agent, sclerosing agent,and/or growth factor, injected into the soft palate; (j) surgicalimplants containing hydroxyapatite, calcium phosphate (such as VITOSS),or calcium sulfate, alone or loaded with a fibrosis-inducing agent,sclerosing agent, and/or growth factor; (k) other biocompatible tissuefillers, such as those made by BioCure, 3M Company and Neomend, eitheralone, or loaded with a fibrosis-inducing agent, sclerosing agent,and/or growth factor; (l) polysaccharide gels such as the ADCON seriesof gels, either alone, or loaded with a fibrosis-inducing agent,sclerosing agent, and/or growth factor; (m) films, sponges or meshessuch as INTERCEED, VICRYL mesh, and GELFOAM either alone, or loaded witha fibrosis-inducing agent, sclerosing agent, and/or growth factor and/or(n) a hydrogel that is formed from an amino-functionalized polyethyleneglycol (e.g., 4-armed tetra-amino PEG [10k]) and a 4-armed NHSfunctionalized PEG (e.g., pentaerythritol poly(ethylene glycol)ethertetra-succinimidyl glutarate [10K]). This hydrogel may further containcollagen, methylated collagen and/or gelatin. This hydrogel can furthercomprise the fibrosis-inducing agents described above (e.g., silk powderor silk threads). Films, sponges, and meshes may be placed into the softpalate. Also of use for injection into the soft palate arenon-degradable polymers such as polyesters (e.g., PET), polyurethanes,silicones, PE, PP, PS, PAA, PMA, silk, blends, copolymers thereof aswell as other known non-degradable polymers that are known in the art.Degradable polymers that can be injected into the soft palate to providetissue support include polyesters, polyanhydrides, poly(anhydrideesters), poly(ester-amides), poly(ester-ureas), polyorthoesters,polyphosphoesters, polyphosphazines, cyanoacrylate polymers, collagen,chitosan, hyaluronic acid, chromic cat gut, alginates, starch,cellulose, cellulose esters, blends and copolymers thereof, as well asother known degradable polymers.

In one embodiment, the injectable polymer system is prepared from a4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and methylated collagensuch as described above. The injectable polymer system may be combinedwith a biologically active agent (e.g., fibrosis-inducing agents such astalc, silk, wool, chitosan, polylysine, fibronectin, bleomycin, CTGF;sclerosing agents such as ethanol, DMSO, surfactants, sucrose, sodiummorrhuate, ethanolamine oleate NaCl, dextrose, glycerin, minocycline,tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate,sodium morrhuate, sotradecol; growth factors such as transforming growthfactor, platelet-derived growth factor, fibroblast growth factor, andbone morphogenic proteins; and/or analogues and derivatives of thesecompounds) and injected into the soft palate. The injectable polymersystem can further comprise agents such as glycerol, glycerin, PEG 200,triethyl citrate, and triacetin as plasticizers.

In another embodiment, the injectable materials delivered to the softpalate can be formulated to be delivered from the catheter (or needle)as a particulate material that has the ability to induce fibrosis. Theinjectable particles can be loaded with, coated with, or comprised of afibrosis-inducing agent. These particles can be either degradable ornon-degradable and are similar in composition to those described above.In addition to the aforementioned polymers, particulate materials usefulfor the practice of this embodiment include talc, starch, glass,silicates, silica, calcium phosphate, calcium sulfate, calciumcarbonate, hydroxyapatite, synthetic mineral (VITOSS and CORTOSS), PMMA,silver nitrate, ceramic particles and other inorganic particles known inthe art to induce a fibroproliferative response. The particles used inthis embodiment can be all of the same composition or a blend ofdiffering compositions. These particles can also be used in combinationwith the injectable polymeric materials described above.

In many of the above embodiments, it may also be useful to add aradio-opaque material (such as tantalum, barium, other metal, orcontrast material) such that the injected material can be visualizedradiographically. Also, when performing direct injection into the softpalate, techniques can be used to enhance visualization of needle (orcatheter) via ultrasound through the use of a needle coated withECHO—COAT or the injection of air (microbubbles).

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agent, sclerosing agent, or growth factormay be utilized alone, or in combination, in the practice of thisembodiment. Exemplary fibrosing agents for use in injectable soft palateimplant procedures include talc, silk, wool, chitosan, polylysine,fibronectin, bleomycin, CTGF, sclerosing agents, and/or growth factors(such as transforming growth factor, platelet-derived growth factor,fibroblast growth factor, bone morphogenic proteins) as well asanalogues and derivatives of the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or a bonemorphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof).

Furthermore, the device may additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

In some clinical situations, repeated injections of the active agentsmay be required. Specific agents and dosages for use in injectable softpalate implants can be described in greater detail in section (iii)below.

(ii) Soft Palate Implants Combined with a Fibrosis-Inducing Agent

Soft palate implants are devices that are designed to be inserted underthe mucosa in the soft palate in the roof of the mouth of a person withsnoring or sleep apnea. Soft palate implants are described in, e.g.,U.S. Pat. Nos. 6,626,181; 6,571,798 and 6,578,580. Other medical devicesused for treating sleep apnea include soft palate implants that provideelectrostimulation (see, e.g., 6,240,316; 6,574,507; 5,284,161 and5,792,067).

Soft palate implants, which may be combined with one or morefibrosis-inducing agents, sclerosing agents and/or growth factorsaccording to the present invention, include several commerciallyavailable products. For example, the PILLAR Palatal Implant System fromRestore Medical Inc. (St. Paul, Minn.) for the treatment of snoring is awoven polyester material implanted into the soft palate that stiffensand supports the palate (thereby reducing vibration and the tendency forthe soft palate to “flop down” and obstruct the airway) without heatingor removing tissue.

Numerous polymeric and non-polymeric carrier systems described above maybe used to deliver fibrosis-inducing agents, sclerosing agents andgrowth factors from soft palate implants. Methods for incorporatingfibrosing, sclerosing and growth factor compositions onto or into softpalate implants include: (a) directly affixing to the palatal implant afibrosing, sclerosing and/or growth factor composition (e.g., by eitherspraying the surface of the implant or dipping the implant into asolution containing the active agent; the agent can be applied alone orwith a polymeric carrier); (b) directly incorporating into thecomponents or the polymers that make up the palatal implant a fibrosing,sclerosing and/or growth factor composition (e.g., by either a sprayingprocess or dipping process with or without a polymeric carrier; (c) bycoating the palatal implant with a substance such as a hydrogel whichcan in turn absorb the fibrosing, sclerosing and/or growth factorcomposition; (d) by interweaving a thread coated with (or composed of) afibrosing, sclerosing and/or growth factor into the structure of thepalatal implant; (e) by inserting the palatal implant into a sleeve ormesh which is comprised of, or coated with, a fibrosing, sclerosingand/or growth factor composition; (f) constructing the palatal implantitself, or a portion of the implant, with a fibrosing, sclerosing and/orgrowth factor composition (particularly effective for silk); and/or (g)by covalently binding the fibrosing agent, sclerosing agent, and/orgrowth factor directly to the palatal implant surface or to a linker(small molecule or polymer) that is coated or attached to the implantsurface. For palatal implants, the coating process can be performed insuch a manner as to: a) coat the exterior surfaces of the implant, b)coat the interior surfaces of the implant or c) coat all or parts ofboth external and internal surface of the implant. In addition tocoating the palatal implant with the fibrosing, sclerosing and/or growthfactor composition, the active agent can be mixed with the materialsthat are used to make the implant such that the fibrosing, sclerosingand/or growth factor is incorporated into the final implant.

It should be apparent to one of skill in the art that potentially anyfibrosis-inducing agent, sclerosing agent or growth factor may beutilized alone, or in combination, in the practice of this embodiment.Exemplary fibrosing agents for use in combination with soft palateimplants include talc, silk, wool, chitosan, polylysine, fibronectin,bleomycin, CTGF; sclerosing agents such as sodium morrhuate,ethanolamine oleate, ethanol, DMSO, surfactants, sucrose, NaCl,dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol,sodium tetradecyl sulfate, sodium morrhuate, sotradecol; and/or growthfactors such as transforming growth factor, platelet-derived growthfactor, fibroblast growth factor, and bone morphogenic proteins, as wellas analogues and derivatives of the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or a bonemorphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof).

Furthermore, the device may additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

In some clinical situations, repeated injections of the active agentsmay be required. Specific agents and dosages for use in injectable softpalate implants can be described in greater detail in section (iii)below.

(iii) Agents for Use in the Management Sleep Apnea

There are several commercially available sclerosing agents which may besuitable for use according to the present invention. One exampleavailable from Wyeth Pharmaceuticals (Collegeville, Pa.), a division ofWyeth (Madison, N.J.), is SOTRADECOL, which is sodium tetradecylsulfate. Other sclerosing agents include sodium morrhuate, ethanolamineoleate, compositions containing ethanol, DMSO, surfactants, sucrose,NaCl, dextrose, glycerin, minocycline, tetracycline, doxycycline,polidocanol, sodium morrhuate, sotradecol and others. Other examples ofcompositions suitable for injection into the soft palate or combiningwith a soft palate implant include silk (e.g., microparticulate silk)and polymeric gels (such as those available from Polymerix Corporation)composed of fibrosis-inducing agents, sclerosing agents, and growthfactors.

Since palatal implants and devices are made in a variety ofconfigurations and sizes (including injectables and implants), the exactdosage administered can vary with the amount injected, or the size,surface area and design of the implant. However, certain principles canbe applied in the application of this art. Drug dose can be calculatedas a function of dose per unit volume/area (of the total volume ofmaterial injected or of the surface area of the portion of the palatalimplant being coated), total drug dose administered can be measured andappropriate surface concentrations of active drug can be determined.Regardless of the method of application of the fibrosis-inducing agentin the management of sleep apnea, the exemplary fibrosing agents, usedalone or in combination, should be administered under the followingdosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered in a soft palate injection, or coatedonto the surface of a palatal implant or device, should not exceed 100mg (range of 1 μg to 100 mg). In one embodiment, the total amount oftalc released should be in the range of 10 μg to 50 mg. The dose perunit volume of a soft palate injectable (i.e., the dosage of talc as afunction of the volume of material injected) should fall within therange of 0.05 μg-10 μg per mm³. In another embodiment, talc should beapplied to a palatal implant or device surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. In one embodiment, talc isreleased from a soft palate injectable, device or implant such thatfibrosis in the tissue is promoted for a period ranging from severalhours to several months. For example, in a preferred embodiment talc maybe released in effective concentrations for a period ranging from 3-12months. It should be readily evident given the discussions providedherein that analogues and derivatives of talc (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as talc isadministered at half the above parameters, a compound half as potent astalc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered in soft palate injection, or coatedonto the surface of a soft palate implant or device, should not exceed100 mg (range of 1 μg to 100 mg). In one embodiment, the total amount ofsilk released should be in the range of 10 μg to 50 mg. The dose perunit volume of a soft palate injectable (i.e., the dosage of silk as afunction of the volume of material injected) should fall within therange of 0.05 μg-10 μg per mm³. In another embodiment, silk should beapplied to a soft palate implant or device surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific soft palateinjectables, implants and devices can release silk at differing rates,the above dosing parameters should be utilized in combination with therelease rate of the drug from the soft palate injectable, implant ordevice such that a minimum concentration of 0.01 nM to 1000 μM of silkis delivered to the tissue. In one embodiment, silk is released from asoft palate injection, implant or device such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, in a preferred embodiment silk may be released ineffective concentrations for a period ranging from 3-12 months. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of silk (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as silk is administered at half theabove parameters, a compound half as potent as silk is administered attwice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered in soft palate injection, or coatedonto the surface of a soft palate implant or device, should not exceed100 mg (range of 1 μg to 100 mg). In one embodiment, the total amount ofchitosan released should be in the range of 10 μg to 50 mg. The dose perunit volume of the soft palate injectable (i.e., the dosage of chitosanas a function of the volume of material injected) should fall within therange of 0.05 μg-10 μg per mm³. In another embodiment, chitosan shouldbe applied to a soft palate implant or device surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific palatal injectables,implants and devices can release chitosan at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the soft palate injectable, implant or device suchthat a minimum concentration of 0.01 nM to 1000 μM of chitosan isdelivered to the tissue. In one embodiment, chitosan is released from ofa soft palate injectable, implant or device such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, in a preferred embodiment chitosan may be releasedin effective concentrations for a period ranging from 3-12 months. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of chitosan (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as chitosan isadministered at half the above parameters, a compound half as potent aschitosan is administered at twice the above parameters, etc.).

Utilizing polylysine as a exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered in soft palate injection, orcoated onto the surface of a soft palate implant or device, should notexceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the totalamount of polylysine released should be in the range of 10 μg to 50 mg.The dose per unit volume of the soft palate injectable (i.e., the dosageof polylysine as a function of the volume of material injected) shouldfall within the range of 0.05 μg-10 μg per mm³. In another embodiment,polylysine should be applied to a soft palate implant or device surfaceat a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificpalatal injectables, implants and devices can release polylysine atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the soft palateinjectable, device or implant such that a minimum concentration of 0.01nM to 1000 μM of polylysine is delivered to the tissue. In oneembodiment, polylysine is released from a soft palate injectable,implant or device such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example, in apreferred embodiment polylysine may be released in effectiveconcentrations for a period ranging from 3-12 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of polylysine (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as polylysine is administered at halfthe above parameters, a compound half as potent as polylysine isadministered at twice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered in soft palateinjection, or coated onto the surface of a soft palate implant ordevice, should not exceed 100 mg (range of 1 μg to 100 mg). In oneembodiment, the total amount of fibronectin released should be in therange of 10 μg to 50 mg. The dose per unit volume of the soft palateinjectable (i.e., the dosage of fibronectin as a function of the volumeof material injected) should fall within the range of 0.05 μg-10 μg permm³. In another embodiment, fibronectin should be applied to a softpalate implant or device surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific soft palate injectables, implants anddevices can release fibronectin at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the soft palate injectable, implant or device such that aminimum concentration of 0.01 nM to 1000 μM of fibronectin is deliveredto the tissue. In one embodiment, fibronectin is released from a softpalate injectable, implant or device such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, in a preferred embodiment fibronectin may be released ineffective concentrations for a period ranging from 3-12 months. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of fibronectin (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as fibrohectin isadministered at half the above parameters, a compound half as potent asfibronectin is administered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered in soft palate injection, orcoated onto the surface of a soft palate implant or device, should notexceed 100 mg (range of 0.01 μg to 100 mg). In one embodiment, the totalamount of bleomycin released should be in the range of 0.10 μg to 50 mg.The dose per unit volume of the soft palate injectable (i.e., the dosageof bleomycin as a function of the volume of material injected) shouldfall within the range of 0.005 μg-10 μg per mm³. In another embodiment,bleomycin should be applied to a soft palate implant or device surfaceat a dose of 0.005 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specific softpalate injectables, implants and devices can release bleomycin atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the soft palateinjectable, implant or device such that a minimum concentration of 0.001nM to 1000 μM of bleomycin is delivered to the tissue. In oneembodiment, bleomycin is released from a soft palate injectable, implantor device such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, in apreferred embodiment bleomycin may be released in effectiveconcentrations for a period ranging from 3-12 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of bleomycin (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as bleomycin is administered at halfthe above parameters, a compound half as potent as bleomycin isadministered at twice the above parameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered in a soft palate injection, or coatedonto the surface of a soft palate implant or device, should not exceed100 mg (range of 0.01 μg to 100 mg). In one embodiment, the total amountof CTGF released should be in the range of 0.10 μg to 50 mg. The doseper unit volume of the soft palate injectable (i.e., the dosage of CTGFas a function of the volume of material injected) should fall within therange of 0.005 μg-10 μg per mm³. In another embodiment, CTGF should beapplied to a soft palate implant or device surface at a dose of 0.005μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific soft palateinjectables, implants and devices can release CTGF at differing rates,the above dosing parameters should be utilized in combination with therelease rate of the drug from the soft palate injectable, implant ordevice such that a minimum concentration of 0.001 nM to 1000 μM of CTGFis delivered to the tissue. In one embodiment, CTGF is released from asoft palate injectable, implant or device such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, in a preferred embodiment CTGF may be released ineffective concentrations for a period ranging from 3-12 months. Itshould be readily evident given the discussions provided herein thatanalogues and derivatives of CTGF (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as CTGF is administered at half theabove parameters, a compound half as potent as CTGF is administered attwice the above parameters, etc.).

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or a bonemorphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof. Bone morphogenic protein(s)(e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue orderivative thereof) are to be used in formulations at concentrationsthat range from 0.001 μg/ml to approximately 20 mg/ml depending on thespecific clinical application, formulation type (e.g., gel, liquid,solid, semi-solid), formulation chemistry, duration of requiredapplication, type of medical device interface and formulation volume andor surface area coverage required. Preferably, the bone morphogenicprotein is released in effective concentrations for a period rangingfrom 1-180 days. The total dose for a single application is typicallynot to exceed 500 mg (range of 0.001 μg to 500 mg); preferred 1 μg to250 mg. When used as a device coating, the dose is per unit area of0.001 μg-1000 μg per mm²; with a preferred dose of 0.01 μg/mm²-200μg/mm². Minimum concentration of 10⁻⁹-10⁻⁴ M of bone morphogenic proteinis to be maintained on the device surface.

Inflammatory cytokines are to be used in formulations at concentrationsthat range from 0.0001 μg/ml to approximately 20 mg/ml depending on thespecific clinical application, formulation type (e.g., gel, liquid,solid, semi-solid), formulation chemistry, duration of requiredapplication, type of medical device interface and formulation volume andor surface area coverage required. Preferably, the inflammatory cytokineis released in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see, e.g., Example 16). The proliferative agents areto be used in formulations at concentrations that range from 0.1 ng/mlto 25 mg/ml depending on the specific clinical application, formulationtype (e.g., gel, liquid, solid, semi-solid), formulation chemistry,duration of required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

12. Embolic Agents and Embolization Devices

In one aspect, the present invention provides for the combination of afibrosing agent with embolization devices and aneurysm coils.Embolization devices are designed to slow or eliminate blood flow to atissue and may be used to treat a variety of medical conditions whichinclude, without limitation, uncontrolled vascular bleeding (such asmenorrhagia), vascular aneurysms (such as thoracic aortic aneurysm,abdominal aortic aneurysms, cerebral aneurysms), benign tumor growth(such as uterine fibroids), malignant tumor growth (particularlyhepatic, renal and other solid tumors) and vascular malformations (AVmalformations, vascular tumors).

Embolization devices refer to devices that are designed to be placedwithin the vasculature (typically an artery) of the patient such thatthe flow of blood through a vessel (or portion of a vessel in the caseof an aneurysm) is largely or completely obstructed. The embolic agentor device can be inserted such that it becomes physically lodged in theartery lumen causing interruption of blood flow to a tissue. The embolicagent or device can also induce clotting in the vessel (or portion of avessel) such that blood flow becomes obstructed by clot (or acombination of the device and clot). In either case, blood supply to aparticular anatomical region (e.g., a tumor, an aneurysm sac, a vascularmalformation) is reduced, or eliminated, leading to ischemic damage orcomplete destruction of the unwanted tissue.

Examples of embolization devices include, without limitation, vascularcoils, vaso-occlusion devices, vascular wires, intravascularembolization devices, vascular occlusion apparatus, microcoils,injectable embolic agents, polymeric embolic agents, embolizing agents,embolic vascular implants, embolic plugs, expandable implants, vascularplugs, vascular endoprostheses and embolic microspheres.

In one aspect, the embolization device is a vascular (vaso-)occlusivedevice. Vaso-occlusion devices can be inserted into the vasculature orsome other region which is to be occluded, such as fallopian tubes andbile ducts. Vaso-occlusion devices may be take a variety of forms. Forexample, the primary shape of a vascular (vaso-)occlusive device may bea in the form of a coil (e.g., a helical coil or spiral), also referredto herein as a vaso-occlusive coil implant. Alternatively, thevaso-occlusive device may be in a non-coil (i.e., non-helical ornon-spiral) form. Representative examples of non-coiled vaso-occlusiveimplants may be in the form of a braid, a random shaped implant, aspherically shaped, ovoid shaped, fibered (see, e.g., U.S. Pat. No.5,226,911), strands, flower-shaped, a sphere, threads, and othernon-helical forms. Helical and non-helical vaso-occlusive devices alsomay have a variety of secondary shapes. Specific examples ofembolization coils and other types of embolization devices are describedin further detail in the following sections.

In one aspect, the vaso-occlusive device may be an expandable vascularocclusion device. Expandable vaso-occlusive devices may include aresilient or shape memory material which will self-expand from itsoperative configuration by its own resilient force or by undergoing aphase transformation when exposed and warmed to body temperature.Alternatively, such devices may include plastically deformable materialwhich may be deformed from its radially compact configuration to itsoperative configuration by application of pressure or force.Alternatively, some of these devices may be inflatable from theirradially compact configuration to their operative configuration. Anexample of an expandable embolization device is a lumen blockingapparatus that includes a blood vessel engaging portion which isoperative to anchor the apparatus to the surrounding wall of the bloodvessel and a radially expandable lumen blocking portion which isoperative to prevent the flow of blood in at least one direction,through the lumen of the blood vessel. (see, e.g., U.S. Pat. No.6,638,293) Upon implantation of the device, the radially expandableportion can expand to an operative configuration wherein the bloodvessel engaging portion of the apparatus will engage the blood vesselwall and the lumen blocking portion of the apparatus will block thelumen of the blood vessel to prevent blood flow in at least onedirection.

Unfortunately, in a significant number of cases blood flow isre-established with time (a process called recanalization) leading totreatment failure. This puts the patient back at risk for thepotentially life-threatening consequences of the condition that wastreated with the initial intervention such as bleeding, aneurysmrupture, cerebral hemorrhage, or tumor growth. Treatment failure occursin some clinical situations in part because currently available agentsdo not produce permanent fibrosis (true luminal scarring where the wallsof the vessel adhere to each other and permanent fibrous tissue occludesthe vessel) leading to the possibility of recanalization,re-establishment of blood flow, and ultimately disease recurrence. Thepresent invention describes the addition of fibrosis-inducing agents tothe materials injected (or devices implanted) into the vasculature forthe purpose of producing a permanent, obstructive scar in the vascularlumen (or aneurysm sac) that results in regression and absorption of theunwanted vessel (or portion of the vessel). If blood flow is permanentlyprevented in the vessel due to obstructive fibrosis, the body can resorbthe non-functioning vascular tissue and can eliminate the blood vessel,leaving little or no chance for recurrence.

(i) Aneurysm “Coils” Combined with a Fibrosis-Inducing Agent

Vascular aneurysms occur due to the focal weakening of a portion of thearterial wall that eventually leads to bulging of the vessel (called ananeurysm “sac”). The thin, weak wall of the aneurysm sac is at anincreased risk for rupturing under the pressure of arterial blood flow;a risk that increases progressively as the sac increases in size.Aneurysm rupture can have catastrophic consequences includingsubarachnoid hemorrhage, stroke, permanent neurological deficits, anddeath for cerebral aneurysms and massive hemorrhage and death for aorticaneurysms. Surgical procedures to treat this condition, especially iflocated in the brain (known as aneurysm “clipping”), can be extremelyrisky or even impossible, depending upon the anatomical location of theaneurysm. As an alternative to surgery, minimally invasive interventionshave been developed whereby both ruptured and unruptured aneurysms canbe treated using embolization devices. Embolization devices may bedelivered to the aneurysm using a catheter or guide-wire that isadvanced from the groin to the area of the aneurysm. The embolizationdevice is then inserted through the catheter and into the aneurysm. Oncewithin the aneurysm, it physically occupies space within the aneurysmsac, induces the formation of clot, “fills” the aneurysm sac, andprevents arterial blood flow from entering the aneurysm and thus,prevents further damage. Numerous implants have been described forinsertion into an aneurysm sac and are suitable for combining with afibrosis-inducing agent. One of the most common treatments for cerebralaneurysms involves the implantation of vascular “coils” (i.e., aneurysmcoil) into the aneurysm sac. The coil is advanced into the sac via adelivery catheter under radiologic guidance, detached (often by theinduction of current in metal coils) from the delivery catheter andreleased into the sac; the procedure is then repeated until enough coilsare “packed” into the aneurysm sac to fill it completely. Although asignificant advancement in the treatment of aneurysms, detachable coilsare not without their limitations. Complications associated with theseprocedures include inadvertent occlusion of the parent artery (occursapproximately 21% of the time), persistent filling of the aneurysm lumen(incomplete occlusion), and recanalization (i.e., return of blood flowinto the aneurysm following initially successful occlusion) rate of 2-5%per year. The consequences of incomplete occlusion (occurring in 38% ofcases for small necked aneurysms, 60-85% of cases for broad neckedaneurysms) and recanalization are that there is an increased risk thatthe aneurysm can rebleed. Specifically, the coil-thrombus complex formedafter initial successful deployment is thought to be unstable.Recanalization can be due to compression of the coil bundle andrearrangement of individual coil loops which have a tendency to revertback to their original helical form (especially when not denselypacked). The clinical result of recanalization is that the patient is atrisk for aneurysm rupture and bleeding (subarachnoid hemorrhage), whichis associated with a high mortality rate (25-50%) and high morbidityrate (50% of survivors have a significant neurologic deficit). Incontrast, completely occluded aneurysms are thought to have a low (orno) risk of rebleeding. The addition of a fibrosis-inducing agent to ananeurysm coil can help reduce the risk of failure by stabilizing thecoil-thrombus complex with fibrous tissue (preventing incompleteocclusion) and filling the sac with permanent scar tissue (preventingrecanalization).

A variety of aneurysm coils can be combined with a fibrosis-inducingagent for the purposes of this invention. It should be obvious to one ofskill in the art that the exact physical shape of the coil is notcritical to the practice of this invention, however, numerous coildesigns are presented by way of illustration. In one aspect, theaneurysm coil may be composed of a biocompatible metal alloy (e.g.,platinum or tungsten) and/or a biocompatible polymer, which may or maynot be biodegradable. In one aspect, aneurysm coils and wires areprovided that are made from a biodegradable material, such as a polymer,which is flexible (malleable) and strong. The polymer may be capable ofexpanding in size after deployment. Representative examples ofexpansible polymers for use in aneurysm coils and wires are crosslinkedpoly(vinyl alcohol), crosslinked poly(ethylene glycol), poly(acrylicacid), poly(hydroxethyl methacrylate), as well as copolymers and blendsthereof. Degradation of the polymeric coil in the days to weeksfollowing deployment has several advantages. For example, polymericaneurysm coils, in contrast to metallic coils, may reduce the risk ofaneurysm performation during deployment. Since the coils do not persist,they also may be less likely to migrate into the parent vesselcirculation. Further, degradable coils can become incorporated into thethrombus-coil complex, thus reducing the incidence of recanalization.

The vascular aneurysm coil may be coated or uncoated, and/or may includeother elements (e.g., strands, filaments, meshes and/or other particles)along the coil. In one aspect, aneurysm coils can be coated with orcontain a non-thrombogenic substance (e.g., heparin, antithrombin,antithrombin-heparin complex), which prevents thrombus from occurringprior to final placement of the device. This temporary coating can bedesigned to persist for minutes to hours depending upon the timerequired to deploy the device.

The aneurysm coil may be composed of a porous, flexible PTFE material,such as expanded PTFE (ePTFE). The PTFE material may take a variety offorms. For example, the material may take the form of a thin strand orribbon and may be reinforced with a metallic strand or a biodegradablepolymeric strand. The PTFE material can be coated with a water-solublepolymer that also may provide some rigidity to the material for deliverypurposes, but, upon dissolution out of the material, the materialbecomes very flexible. The material can be impregnated or coated, withor without the use of a carrier, with one or a combination of fibrosingagents and other biologically active agents (e.g., agents to promotethrombosis or cellular growth). The material may be delivered into theaneurysm using a catheter-based delivery system as described above. Withthe appropriate design, the catheter could deliver fixed lengths of thematerial or could deliver a continuous strand of the material that couldbe cut to the desired length by a cutting device at the end of thecatheter. The material is preferably thin enough so that it is veryflexible and does not exert significant pressure on the aneurysm wallonce deployed. For materials that do not have the structural strength tobe delivered through a catheter, a thin metallic strand can beincorporated into the material to produce a more rigid material. Themetallic strand may be made from, for example, stainless steel,titanium, platinum, gold, nickel, nitinol, or other alloy. Abiodegradable polymeric strand may be used in place of the metallicstrand. Once deployed, the polymeric strand can degrade, therebyeliminating the potential for late strage perforation of the aneurysm.Polymeric strands may be made from, e.g., a polyester (e.g., PLGA, PLA,PCL, PGA, and the like), polyanhydrides, polyorthoesters, tyrosine basedpolymers, polyphosphazines, polyamides (e.g., proteins such as gelatin),carbohydrates, polysaccharides and blends thereof. The strands can beincorporated into the material by threading them through the material orby laminating them between two layers of the material or by thermalfusion into the material. The strand may also be made of anon-degradable polymer such as, for example, a polyurethane, silicone,PE, PP, polyacrylate or poly(methacrylate) based polymer, polyamidepolymer, or vinyl based polymer. The material may also be made morerigid by incorporating a polymer into the pores of the material. Thispolymer may be either water-soluble or water insoluble and may bebiodegradable or non-degradable. An example of a water-soluble,non-degradable polymer is PEG. A tyrosine based polymer such as DTE isan example of a water-insoluble polymer that has a relatively shortdegradation time. Polymers may be used to supply some degree ofstructural rigidity for the deployment process by filling the pores ofthe porous PTFE but would degrade or dissolve rapidly after deployment,such that the material would revert to its flexible state and can bepacked into the aneurysm sac more densely.

The vascular coil may be composed of a bioactive component or may bebiologically inert. Since vascular coils may be delivered through amicrocatheter to the vascular site, they may be designed to have both aprimary phase and a secondary phase. The phases of the vascular coil maybe characterized by a different shape or configuration, composition,physical state and/or level of bioactivity. Typically, these phasesrepresent the state of the vascular coil prior to insertion (i.e.,primary phase) and then the state of the vascular coil post-insertion(i.e., secondary phase). For example, the vascular coil may be designedas an outer helically wound device having a stretch-resistant polymericfilament in which a secondary shape is formed and heat-treated topreserve that form. See e.g., U.S. Pat. No. 6,193,728. The vascular coilmay be designed to be a linear helical configuration when stretched, anda folded, convoluted configuration when relaxed. See e.g., U.S. Pat. No.4,994,069. The vascular coil may be composed of a flexible, helicallywound coil having two primary coil ends and a primary diameter which ina relaxed secondary configuration comprises at least two longitudinalfocal axes. See e.g., U.S. Pat. No. 5,639,277. The vascular coil mayhave attached fibrous elements which extend in a sinusoidal fashion downthe length of the coil and thus, produce a variety of secondary shapes.See e.g., U.S. Pat. No. 5,304,194. The vascular coil may be a metal coilthat has one or more fiber bundles having a serpentine configuration inwhich the loops extend about the individual windings of the coil. Seee.g., U.S. Pat. No. 5,226,911. The embolization device (e.g., vascularcoil) may be composed of a helical coil having a multiplicity ofwindings that define a lumen and a plug of thermoplastic biocompatiblepolymer that is located at the ends of the coil into the lumen space.See e.g., U.S. Pat. No. 5,690,667. The vascular coil may be composed ofan elongated helical coil of a biocompatible metal having a plurality ofaxial spaced windings and a plurality of strands of a polymeric,bioactive, occlusion-causing material extending axially through thecoil. See e.g., U.S. Pat. No. 5,658,308. The embolization device may bean expandable support element having a relaxed expanded state and astretched collapsed state, and an embolization element which is mountedon the support element which serves to substantially prevent the bloodflow (e.g., polymer mesh). See e.g., U.S. Pat. No. 6,554,849. Theembolization device may be composed of an elongated, flexiblefilamentous carrier and an embolizing element in the form of anexpansile polymer (e.g., porous hydrogel) which is fixed to the carrier.See e.g., U.S. Pat. No. 6,602,261. The vascular coil may contain apositive charge, electric current, or magnetic field on the coil whichpromotes embolization. See e.g., U.S. Pat. Nos. 5,122,136, 6,066,133 and6,603,994. Other vascular types of coils are described in, e.g., U.S.Pat. Nos. 5,133,731; 5,312,415; 5,354,294; 5,382,259; 5,382,260;5,417,708; 5,423,849; 5,476,472; 5,578,074; 5,582,619; 5,624,461;5,645,558 and 5,718,711.

Aneurysm coils, which may be combined with one or more fibrosis-inducingagents according to the present invention, include several commerciallyavailable products. For example, the GDC (GUGLIELMI DETACHABLE COIL) andthe MATRIX detachable coils (from Boston Scientific Corporation) areparticularly useful for the practice of this embodiment. The MICROPLEXand HYDROCOIL Coil System (from MicroVention, Inc., Aliso Viejo,Calif.), TORNADO Embolization Microcoils from Cook Diagnostic andInterventional Products (Bloomington, Ind.), HELIPAQ helical andMICRUSPHERE spherical coils from Micrus Corp. (Sunnyvale, Calif.), theGDC Coils 2D and 3D from Target Therapeutics, Inc. (Fremont,Calif.)/Boston Scientific Corporation, and the TRUFILL Pushable Coilsfrom Cordis Corporation (Miami Lakes, Fla.)/Johnson & Johnson are alsosuitable.

Several injectable polymeric systems and embolization agents have beendescribed for injection into the aneurysm sac for the treatment ofcerebral and thoracic aneurysm. These vascular “fillers” are furtherdescribed in section (ii) below. Vascular polymeric implants can becombined with a fibrosis-inducing agent for the purposes of thisinvention in the treatment of aneurysms. It should be obvious to one ofskill in the art that the composition of the polymeric aneurysm implantis not critical to the practice of this invention.

Numerous polymeric and non-polymeric carrier systems described above maybe used to deliver fibrosis-inducing agents from implantable aneurysmtreatments such as coils and polymeric implants. Methods forincorporating fibrosis-inducing compositions onto or into aneurysm coilsand implants include: (a) directly affixing to the aneurysm coil orimplant a fibrosing composition (e.g., by either spraying the surface ofthe implant or dipping the implant into a solution containing the activeagent; the agent can be applied alone or with a polymeric carrier); (b)directly incorporating a fibrosing composition into the components orthe polymers that make up the aneurysm coil or implant (e.g., by eithera spraying process or dipping process with or without a polymericcarrier—particularly effective for coils that have polymeric componentssuch as coatings, meshes and hydrogels described above); (c) by coatingthe aneurysm coil or implant with a substance such as a hydrogel whichcan in turn absorb the fibrosing composition; the hydrogel can alsoswell to better fill the aneurysm sac; (d) by interweaving or attaching“threads” coated with (or composed of—particularly in the case of silk)a fibrosing agent into the structure of the aneurysm coil or implant;the threads in turn can be branched or “arborized” to increase thesurface area; (e) by inserting the aneurysm coil or implant into asleeve or mesh which is comprised of, or coated with, a fibrosingcomposition; (f) constructing the aneurysm coil or implant itself, or aportion of the coil or implant, with a fibrosing composition(particularly effective for polymeric drug compositions, silk andEVA—e.g., to create a silk and/or EVA aneurysm coil); this has the addedbenefit of creating a “floppy coil” that can not perforate through theweakened aneurysm wall (aneurysm perforation by metallic coils occurs in5% of cases); the floppy coil can be further coated with hard polymersurface (to provide stiffness during deployment) that dissipates quicklyafter deployment to leave behind a floppy coil; in a particularlypreferred embodiment, the aneurysm coil is composed of silk and/or EVAbackbone with multiple “branches” of silk and/or EVA emanating from itto increase surface area (there can be branches upon branches; i.e.,multiple generations of arborizations); or (g) by covalently binding thefibrosing agent directly to the aneurysm coil or implant surface or to alinker (small molecule or polymer) that is coated or attached to thesurface. For aneurysm coils and implants, the coating process can beperformed in such a manner as to: (a) coat the exterior surfaces of thedevice; (b) coat the interior surfaces of the device, (c) coat all orparts of both external and internal surface of the device, or (d) coatthe coil with a non-thrombogenic substance (e.g., heparin, antithrombin,antithrombin-heparin complex) which prevents thrombosis from occurringprior to final placement of the device and then dissipates to allowthrombosis to occur. In addition to coating the aneurysm coil or implantwith the fibrosing composition, the active agent can be mixed with thematerials that are used to make the coil or implant such that thefibrosing agent is incorporated into the final implant.

In one embodiment, the aneurysm coil may include a starch (e.g., cornstarch or maize starch). The starch material may be incorporated intothe device as a coating and/or in combination with polymeric threads(e.g., silk) that are attached to the aneurysm coil. The starch or astarch-containing composition may be coated onto the device by applyingstarch powder directly to the device surface. Alternatively, the starchcan be applied to the device using a solvent process or an extrusionprocess. The entire device or only a portion of the device may be coatedwith the starch. For example, starch can be made into a solution (e.g.,by placing a 5% aqueous solution in an autoclave for 45 min.) which canbe coated onto the outer surface of the device. The solvent then isremoved to leave the starch coated on the device. In another approach,the starch can be incorporated into a secondary carrier (e.g., adegradable or non-degradable polymer, wax, lipid, oil, and the like),which may, optionally, be cross-linked. The secondary carrier (e.g.,polymer) can be coated onto the device. In another aspect, the starchmay be incorporated into or onto a non-degradable polymer (e.g., silk orDACRON) or biodegradable polymer (e.g., PLGA) which is then coated ontothe device. As the polymer degrades, the starch is released to thesurrounding tissue where it may cause the desired biological response.Alternatively, or in addition, the starch may be incorporated into thematerials used to make the device.

The aneurysm coil may include polymeric threads, such that the presenceof the polymeric threads results in an enhanced cellular andextracellular matrix response to the exterior of the device. Thepolymeric threads can be made from any polymer that results in anenhanced cellular and/or fibrotic response. For example, the threads maybe a silk suture material or another type of biocompatible polymer(e.g., starch) which is coated with a polymer that results in anenhanced cellular response. The polymeric threads can be attached to theaneurysm coil in various configurations that may result in eitherpartial or complete coverage of the exterior of the aneurysm coil. Anycombination of the above methods may be used in the practice of thisembodiment.

The fibrosing agent containing threads may be attached to the aneurysmcoil using any appropriate method, e.g., an adhesive, thermal welding,stitching, wrapping, weaving, knotting, or a combination of any of thesemethods.

The threads can be coated with a material that delays the time it takesfor the thread material to come into contact with the surroundingtissue. This allows for placement of the device without concern ofthrombotic events as a result of the polymeric threads. Coatings may befrom degradable materials that dissolve once implanted (e.g., gelatin,polyesters, such as PLGA, PLA, MePEG-PLGA, PLGA-PEG-PLGA, and copolymersand blends thereof, lipids, fatty acids, sugar esters, nucleic acidesters, polyanhydrides, polyorthoesters, PVA, and the like). Thesecoatings may include a fibrosis-inducing agent and/or an agent thatreduces the probability of an immediate thrombotic event (e.g., heparinand heparin derivatives, such as hydrophobic quaternary amine heparincomplexes).

It should be apparent to one of skill in the art that potentially anyfibrosis-inducing agent may be utilized alone, or in combination, in thepractice of this embodiment. Exemplary fibrosing agents for use incombination with aneurysm coils and implants include talc, silk, wool,chitosan, polylysine, fibronectin, bleomycin, and CTGF as well asanalogues and derivatives of the aforementioned. These can be furthercombined with other agents such as sclerosing agents (sodium morrhuate,ethanolamine oleate, ethanol, DMSO, surfactants, sucrose, NaCl,dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol,sodium tetradecyl sulfate, sodium morrhuate, sotradecol) and/or growthfactors (transforming growth factor, platelet-derived growth factor,fibroblast growth factor, and bone morphogenic proteins) to furtherenhance efficacy.

Optionally, the device may additionally comprise an inflammatorycytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-a, IL-1,IL-1-β, IL-8, IL-6, and growth hormone) and/or a bone morphogenicprotein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or ananalogue or derivative thereof).

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

(ii) Embolization Agents Containing a Fibrosis-Inducing Agent

Embolization products are used to reduce or eliminate blood flow to aparticular organ or tissue. Typically they are used in the treatment ofbleeding (e.g., embolization of the uterine artery for the management ofsevere menorrhagia), benign tumor growth (e.g., uterine fibroidembolization), malignant tumor growth (hepatic tumors, renal cellcarcinoma, solid tumors), varicoseals, or to treat abnormal vascularstructures (arterio-venous malformations, vascular tumors). Classicallythe procedure is performed by inserting a catheter into the vasculature(often the femoral artery), advancing it under radiologic guidance tothe artery that supplies the tissue to be embolized, advancing adelivery catheter over the guidewire, and deliveringparticles/microspheres/gels into the lumen of the vessel that travel inthe blood stream until they become lodged in a downstream vessel (whosecaliber is smaller than that of the embolic particle). This obstructsthe blood flow to the target tissue, starves it of oxygen and nutrients,leads to ischemia and, in some cases, tissue necrosis and death.

Numerous particles, microspheres and injectable polymer systems havebeen described for vascular injection as embolic agents and are suitablefor combining with a fibrosis-inducing agent. Although initiallysuccessful in occluding blood flow, many embolic agents are able tosustain their efficacy due to recanalization of the treated vessel(i.e., return of blood flow through the artery following initiallysuccessful occlusion). As a consequence of recanalization, there is anincreased risk that bleeding can recur or tumor growth can resume. Incontrast, completely occluded blood vessels are thought to have a low(or no) risk of rebleeding and force tumor cells to recruit newvasculature to the tissue. The addition of a fibrosis-inducing agent toan embolization agent can help reduce the risk of failure by filling thearterial lumen with permanent scar tissue (preventing recanalization).If blood flow is obstructed for a prolonged period of time due toobstructive fibrosis, the vessel regresses, the body resorbs thenonfunctioning vascular tissue, the blood vessel is eliminated and therisk of recurrence is reduced.

Embolization agents, which may be combined with one or morefibrosis-inducing agents according to the present invention, includeseveral commercially available products. For example, the TRUFILLn-Butyl Cyanoacrylate (n-BCA) Liquid Embolic System (Cordis, a divisionof Johnson and Johnson, Miami, Fla.); EMBOSPHERE Microspheres andEMBOGOLD Microspheres (Biosphere, Rockland, Mass.); and the ONYX LiquidEmbolic System (Micro Therapeutics, Irvine, Calif.) are all polymericembolization systems suitable for combining with a fibrosis-inducingagent. Other examples of suitable embolization devices includepolymer/solvent systems containing a fibrosis-inducing agent in whichthe solvent diffuses from the polymer matrix once it has been injectedat the treatment site (e.g., the degradable polymeric systems fromAtrix, non-degradable polymeric compositions such as ONYX and EMBOLYX,and in situ forming materials such as those available from Biocure,Angiotech Pharmaceuticals, Inc., 3M Company and Neomend). Other types ofcommercially available embolic agents that can be loaded or made with afibrosis-inducing agent include PVA particles (Cook, Inc. andAngiodynamics, Inc.) and microsphere formulations (e.g., EMBOSPHERE fromBiosphere, Inc., Contour SE from Boston Scientific and BEAD BLOCK fromBiocompatibles).

Numerous other vascular occlusion devices can be combined with afibrosis-inducing agent. The embolization device may be composed of anexpandable implant or plug that is guided into the vascular site anddetached at the desired location. For example, the expandable implantmay be a balloon delivered by an intravascular catheter which acts as anembolization element when it is inflated with solidifying fluid (e.g.,polymerizing resin or gel). See e.g., U.S. Pat. No. 4,819,637. Theexpandable vascular implant can be composed of hydrogel stent that isguided to the vascular site using a microcatheter and then hydrated andexpanded until it occludes the vessel. See e.g., U.S. Pat. No.5,258,042. Polymeric foams (e.g., polyvinyl alcohol, polyurethane foamor polyethylene foam), pellets or particles that expand to inducevascular occlusion upon exposure to blood fluids (see e.g., U.S. Pat.No. 5,823,198) are also suitable for combining with fibrosis-inducingagents. Another suitable expandable implant is composed of a pluralityof expansible embolizing elements and an elongated filamentous carrier(formed from a flexible material with an elastic memory shaped into alooped structure whereby the elements are released from spaced intervalsalong the loop; see e.g., U.S. Pat. No. 6,238,403).

Injectable liquid embolic agents that change their physical properties(e.g., solidify and/or expand) in response to heating, enzymaticreactions and/or chemical polymerization can be combined withfibrosis-inducing agents. Injectable embolic agents that are an emulsionof particles or microspheres and coagulate with blood components and/orcoalesce with each other at the vascular site can also be utilized. Forexample, the embolic agent may be composed of a cellulose diacetatepolymer, a biocompatible solvent and a water insoluble contrasting agentwhich, when delivered, the solvent disperses into the bloodstream andleaves the remaining components behind to form into a gel that embolizesthe vessel. See e.g., U.S. Pat. No. 5,580,568. Another suitable embolicagent is composed of a polymer and a solvent that is a liquid at bodytemperature and precipitates into a solid in situ in the presence of anon-particulate agent (e.g., vascular coil). See e.g., U.S. Pat. No.6,017,977. Still another suitable embolic agent is composed of athermosensitive polymer delivered as an aqueous solution at onetemperature (i.e., above or below body temperature) that forms into asolid after warming up to (or cooling down to) body temperature. Seee.g., U.S. Pat. No. 5,525,334. Still another suitable liquid embolicagent is an emulsion (composed of an aqueous matrix base and a liquidoil) which forms into an insoluble matrix by either heating, anenzymatic reaction, or chemical polymerization. See e.g., U.S. Pat. No.5,894,022. The embolic agent may also be an injectable solution ofmicrospheres composed of a copolymer coated with a cell adhesionpromoter. See e.g., U.S. Pat. No. 5,648,100. Additional materials thatare used as injectable liquid embolic agents are described in U.S. Pat.Nos. 4,551,132 and 4,795,741.

In one aspect, the present invention provides embolization agentscombined with a fibrosis-inducing agent directly, or a composition(e.g., a polymeric or non-polymeric carrier) that includes a fibrosingagent, for the purpose of permanently occluding a blood vessel. Thefibrosis-inducing agent can be delivered with the embolization agent inseveral ways, including: (a) fluids, suspensions, emulsions,microemulsions, microspheres, pastes, gels, microparticulates, sprays,aerosols, solid implants and other formulations (see those describedabove) which release a fibrosis-inducing agent(s); (b) microparticulatesilk and/or silk strands (linear, branched, and/or coiled) either alone,or loaded with an additional fibrosis-inducing agent (or embolicmaterial) and injected as an embolic agent; (c) gels, microspheres, ormicroparticles formed from polymeric formulations of fibrosing agents(e.g., polymeric drugs such as those described by PolymerixCorporation); (d) fibrosis-inducing agents coated on the surface ofmicrospheres or microparticles, with or without a polymeric carrier; (e)fibrosis-inducing agents loaded into one or more phases of a liquidembolic system (see descriptions above); (f) fibrosis-inducing agentsdelivered in the aqueous phase (i.e., as an infusion into the treatedtissue) in conjunction with (before, during or after) an embolizationprocedure; (g) for in situ forming embolic compositions, thefibrosis-inducing agents can be incorporated directly into theformulation as a suspension or a solution (e.g., silk powder,bleomycin), or loaded into a secondary carrier (e.g., micelles,liposomes, microspheres, microparticles, nanospheres, microparticulates,emulsions and/or micromulsions) that is then incorporated into the insitu forming compositions; (h) the fibrosis-inducing agent can beelectrostatically or covalently bound to one or more of the polymericcomponents of the in situ forming embolization composition; and/or (i)the fibrosing agent can be mixed with the materials that are used tomake the device such that the fibrosing agent is incorporated into theembolic agent during manufacturing (for example, silk powder can beadded as a reagent during the manufacture of microspheres).

It should be apparent to one of skill in the art that potentially anyfibrosis-inducing agents described above may be utilized alone, or incombination, in the practice of this embodiment. Exemplary fibrosingagents for use in embolization devices and compositions include talc,silk, wool, chitosan, polylysine, fibronectin, bleomycin, and CTGF, aswell as analogues and derivatives of the aforementioned.

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or a bonemorphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof).

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.

In some clinical situations, repeated injections of the active agentsmay be required. Specific agents and dosages for use in aneurysm coilsand implants can be described in greater detail in section (iii) below.

(iii) Agents for Use in Embolic Agents and Aneurysm Coils

As embolization agents and aneurysm treatment devices are made in avariety of configurations and sizes, the exact dose administered canvary with implant or device size, surface area and design. However,certain principles can be applied in the application of this art. Drugdose can be calculated as a function of dose per unit area (of theportion of the embolic material or aneurysm device being coated), totaldrug dose administered can be measured and appropriate surfaceconcentrations of active drug can be determined. Regardless of themethod of application of the drug to the embolization or aneurysmdevice, the exemplary fibrosing agents, used alone or in combination,should be administered under the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered from an embolization agent or aneurysmdevice, or coated onto the surface of an embolization or aneurysmdevice, should not exceed 100 mg (range of 1 μg to 100 mg). In oneembodiment, the total amount of talc released from the embolizationagent or aneurysm coil should be in the range of 10 μg to 50 mg. Thedose per unit area of the embolic agent or aneurysm device (i.e., thedosage of talc as a function of the surface area of the portion of theimplant or device to which drug is applied and/or incorporated) shouldfall within the range of 0.05 μg-10 μg per mm² of surface area coated.In another embodiment, talc should be applied to an embolization agentor aneurysm device surface at a dose of 0.05 μg/mm²-10 μg/mm² of surfacearea coated. In one embodiment, talc is released from the surface of anembolization or aneurysm device such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, talc may be released in effective concentrations for a periodranging from 1-9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of talc (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent astalc is administered at half the above parameters, a compound half aspotent as talc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered from an embolization agent or aneurysmdevice, or coated onto the surface of an embolization agent or aneurysmdevice, should not exceed 100 mg (range of 1 μg to 100 mg). In oneembodiment, the total amount of silk released from the embolizationagent or aneurysm coil should be in the range of 10 μg to 50 mg. Thedose per unit area of the implant or device (i.e., the dosage of silk asa function of the surface area of the portion of the device to whichdrug is applied and/or incorporated) should fall within the range of0.05 μL-10 μg per mm² of surface area coated. In another embodiment,silk should be applied to an embolization or aneurysm device surface ata dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificembolization agents and aneurysm devices can release silk at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the embolization or aneurysmdevice such that a minimum concentration of 0.01 nM to 1000 μM of silkis delivered to the tissue. In one embodiment, silk is released from thesurface of an embolization or aneurysm device such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, silk may be released in effective concentrationsfor a period ranging from 1-9 months. It should be readily evident giventhe discussions provided herein that analogues and derivatives of silk(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as silk is administered at half the above parameters, a compoundhalf as potent as silk is administered at twice the above parameters,etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered from an embolization agent oraneurysm device, or coated onto the surface of an embolization agent oraneurysm device, should not exceed 100 mg (range of 1 μg to 100 mg). Inone embodiment, the total amount of chitosan released from the embolicagent or aneurysm coil should be in the range of 10 μg to 50 mg. Thedose per unit area of the device (i.e., the dosage of chitosan as afunction of the surface area of the portion of the implant or device towhich drug is applied and/or incorporated) should fall within the rangeof 0.05 μg-10 μg per mm² of surface area coated. In another embodiment,chitosan should be applied to an embolization or aneurysm device surfaceat a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificimplants and devices can release chitosan at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the embolization or aneurysm device such that aminimum concentration of 0.01 nM to 1000 μM of chitosan is delivered tothe tissue. In one embodiment, chitosan is released from the surface ofan embolization or aneurysm device such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, chitosan may be released in effective concentrations for aperiod ranging from 1-9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of chitosan(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as chitosan is administered at half the above parameters, acompound half as potent as chitosan is administered at twice the aboveparameters, etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered from an embolization agent oraneurysm device, or coated onto the surface of an embolization agent oraneurysm device, should not exceed 100 mg (range of 1 μg to 100 mg). Inone embodiment, the total amount of polylysine released from theembolization agent or aneurysm coil should be in the range of 10 μg to50 mg. The dose per unit area of the device (i.e., the dosage ofpolylysine as a function of the surface area of the portion of theimplant or device to which drug is applied and/or incorporated) shouldfall within the range of 0.05 μg-10 μg per mm² of surface area coated.In another embodiment, polylysine should be applied to an embolizationor aneurysm device surface at a dose of 0.05 μg/mm²-10 μg/mm² of surfacearea coated. As specific (polymeric and non-polymeric) drug deliveryvehicles and specific embolization agents and aneurysm devices canrelease polylysine at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe embolization or aneurysm device such that a minimum concentration of0.01 nM to 1000 μM of polylysine is delivered to the tissue. In oneembodiment, polylysine is released from the surface of an embolizationor aneurysm device such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example,polylysine may be released in effective concentrations for a periodranging from 1-9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of polylysine(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as polylysine is administered at half the above parameters, acompound half as potent as polylysine is administered at twice the aboveparameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered from an embolizationagent or aneurysm device, or coated onto the surface of an embolizationagent or aneurysm device, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of fibronectin released fromthe embolization agent or aneurysm coil should be in the range of 10 μgto 50 mg. The dose per unit area of the device (i.e., the dosage offibronectin as a function of the surface area of the portion of theimplant or device to which drug is applied and/or incorporated) shouldfall within the range of 0.05 μg-10 μg per mm² of surface area coated.In another embodiment, talc should be applied to an embolization agentor aneurysm device surface at a dose of 0.05 μg/mm²-10 μg/mm² of surfacearea coated. As specific (polymeric and non-polymeric) drug deliveryvehicles and specific embolization agents and aneurysm devices canrelease fibronectin at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe embolization or aneurysm device such that a minimum concentration of0.01 nM to 1000 μM of fibronectin is delivered to the tissue. In oneembodiment, fibronectin is released from the surface of an embolizationagent or aneurysm device such that fibrosis in the tissue is promotedfor a period ranging from several hours to several months. For example,fibronectin may be released in effective concentrations for a periodranging from 1-9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives offibronectin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as fibronectin is administered at half theabove parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered from an embolization agent oraneurysm device, or coated onto the surface of an embolization agent oraneurysm device, should not exceed 100 mg (range of 0.01 μg to 100 mg).In one embodiment, the total amount of bleomycin released from theembolization agent or aneurysm coil should be in the range of 0.10 μg to50 mg. The dose per unit area of the device (i.e., the dosage ofbleomycin as a function of the surface area of the portion of theimplant or device to which drug is applied and/or incorporated) shouldfall within the range of 0.005 μg-10 μg per mm² of surface area coated.In another embodiment, bleomycin should be applied to an embolizationagent or aneurysm device surface at a dose of 0.005 μg/mm²-10 μg/mm² ofsurface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific embolization agents and aneurysm devicescan release bleomycin at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe an embolization or aneurysm device such that a minimum concentrationof 0.001 nM to 1000 μM of bleomycin is delivered to the tissue. In oneembodiment, bleomycin is released from the surface of an embolization oraneurysm device such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example,bleomycin may be released in effective concentrations for a periodranging from 1-9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of bleomycin(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as bleomycin is administered at half the above parameters, acompound half as potent as bleomycin is administered at twice the aboveparameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered from an embolization agent or aneurysmdevice, or coated onto the surface of an embolization agent or aneurysmdevice, should not exceed 100 mg (range of 0.01 μg to 100 mg). In oneembodiment, the total amount of CTGF released from the embolizationagent or aneurysm coil should be in the range of 0.10 μg to 50 mg. Thedose per unit area of the implant or device (i.e., the dosage of CTGF asa function of the surface area of the portion of the device to whichdrug is applied and/or incorporated) should fall within the range of0.005 μg-10 μg per mm² of surface area coated. In another embodiment,CTGF should be applied to an embolization agent or aneurysm devicesurface at a dose of 0.005 μg/mm²-10 μg/mm² of surface area coated. Asspecific (polymeric and non-polymeric) drug delivery vehicles andspecific embolization agents and aneurysm devices can release CTGF atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the embolizationagent or aneurysm device such that a minimum concentration of 0.001 nMto 1000 μM of CTGF is delivered to the tissue. In one embodiment, CTGFis released from the surface of an embolization agent or aneurysm devicesuch that fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, CTGF may be released ineffective concentrations for a period ranging from 1-9 months. It shouldbe readily evident given the discussions provided herein that analoguesand derivatives of CTGF (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as CTGF is administered at half theabove parameters, a compound half as potent as CTGF is administered attwice the above parameters, etc.).

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or a bonemorphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof).

Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof) are to be used informulations at concentrations that range from 0.001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the bone morphogenic protein is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.001μg to 500 mg); preferred 1 μg to 250 mg. When used as a device coating,the dose is per unit area of 0.001 μg-1000 μg per mm²; with a preferreddose of 0.01 μg/mm²-200 μg/mm². Minimum concentration of 10⁻⁹-10⁻⁴ M ofbone morphogenic protein is to be maintained on the device surface.

Inflammatory cytokines are to be used in formulations at concentrationsthat range from 0.0001 μg/ml to approximately 20 mg/ml depending on thespecific clinical application, formulation type (e.g., gel, liquid,solid, semi-solid), formulation chemistry, duration of requiredapplication, type of medical device interface and formulation volume andor surface area coverage required. Preferably, the inflammatory cytokineis released in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (Example 16). The proliferative agents are to be usedin formulations at concentrations that range from 0.01 ng/mL to 25 mg/mldepending on the specific clinical application, formulation type (e.g.,gel, liquid, solid, semi-solid), formulation chemistry, duration ofrequired application, type of medical device interface and formulationvolume and or surface area coverage required. Preferably, theproliferative agent is released in effective concentrations for a periodranging from 1-180 days. The total dose for a single application istypically not to exceed 500 mg (range of 0.0001 μg to 200 mg); preferred0.001 μg to 100 mg. When used as a device coating, the dose is per unitarea of 0.00001 μg-500 μg per mm²; with a preferred dose of 0.0001μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

13. Pulmonary Sealants

The present invention provides compositions and devices for use aspulmonary sealants during open or endoscopic lung reduction surgeries.The primary clinical application for pulmonary sealants is in thetreatment of postoperative air leak in the lung. If air is able to leakfrom the lung into the plural space via small holes created duringsurgery, it can build up, exert pressure on the lung, and prevent thelung from fully expanding during inhalation. This prevents normalventilation from occurring, and if severe, can create a medicalemergency that requires urgent drainage of the air trapped in the pluravia a chest tube inserted through the ribs and into the air pocket. Forexample, persistent air leakage is a frequent complication after open orendoscopic pulmonary resection for lung cancer or emphysema and cancause serious complications, such as empyema, chest tube insertion andprolonged hospitalization. Surgical sealants of different types havebeen developed for application to the lung surface to prevent or toreduce postoperative air leaks. The addition of a fibrosis-inducingagent to a pulmonary sealant can induce the formation of a stable,fibrous scar that permanently seals the parietal surface of the lung atthe surgical location (or the alveolar surface of the lung if deliveredendoscopically during lung reduction surgery), reduces hospitalizationtime and prevents recurrence of the air leak. Clinically afibrosis-inducing pulmonary sealant can be useful to improve theoutcomes in open lung surgery, endoscopic lung reduction surgery foremphysema (severe COPD), esophageal leaks after endoscopy or resection,complications of treatment of other intra-thoracic malignancies, pleuraleffusion, haemothorax, pneumothorax, chylothorax, complications ofaspiration, and tuberculosis.

As used herein, the term “sealant” refers to a material which decreasesor prevents the migration of fluid or air from one tissue cavity (e.g.,the lung) to another tissue cavity (e.g., the plural space). Sealantsare typically formed by the application of precursor molecules to atissue followed by local in situ polymerization. The same sealantmaterials may also be used to “glue” tissues together, both when appliedbetween them and then polymerized, or when used simultaneously andembedded between tissues. Generally, surgical sealants are absorbablematerials used primarily to control internal bleeding and to seal tissue(to prevent leakage).

Sealant material and devices for delivering sealant materials for use inthe present invention are described, e.g., in U.S. Pat. Nos. 6,624,245;6,534,591; 6,495,127; 6,482,179; 6,458,889; 6,323,278; 6,312,725;6,280,727; 6,277,394; 6,166,130; 6,110,484; 6,096,309; 6,051,648; and5,874,500; 6,063,061; 5,895,412; 5,900,245 and 6,379,373. Theperformance of these materials may be enhanced through the addition of afibrosis-inducing agent.

In one aspect, the present invention provides lung sealants thatcomprise a fibrosis-inducing agent. Numerous polymeric and non-polymericcarrier systems described above may be used in the practice of thisembodiment. These compositions can further comprise one or morefibrosis-inducing agents to promote the formation of granulation tissue.One example of an appropriate sealant is prepared from a 4-armed thiolPEG (10K), a 4-armed NHS PEG(10K) and methylated collagen such asdescribed above. Commercially available sealants suitable for combiningwith one or more fibrosis-inducing agents according to the presentinvention include: COSEAL; FLOSEAL; SPRAYGEL or a variation thereof; andFOCALSEAL.

In one aspect of the present invention, a fibrosing (i.e., scarring)agent can be included in a polymeric sealant spray which solidifies intoa film or coating to promote fibrosis and seal air leaks. In anotheraspect, a sprayable fibrosis-inducing lung sealant may be used to sealoff pulmonary bullae in open and endoscopic lung destruction procedures.In another embodiment, the spray includes a tissue adherent polymercontaining a fibrosis-inducing agent and may be prepared frommicrospheres.

For sprayable in situ forming compositions, the fibrosis-inducing agentcan be incorporated directly into the formulation to produce asuspension or a solution (e.g., silk powder, bleomycin), or they can beincorporated into a secondary carrier (e.g., micelles, liposomes,microspheres, microparticles, nanospheres, microparticulates, emulsionsand/or microemulsions) that is then incorporated into the in situforming compositions.

In another embodiment, the fibrosis-inducing agent can beelectrostatically or covalently bound to one or more of the polymericcomponents of the in situ forming composition.

In another embodiment, the fibrosis-inducing agent can be incorporateddirectly, or via a secondary carrier, into a gel or thermogel (e.g.,hyaluronic acid, PLURONIC F127, polyester-PEG-polyester (e.g.,PLGA-PEG-PLGA)). These gels can then be applied to the treatment siteprior to, or after, the application of a pulmonary sealant.

In another embodiment, the fibrosis-inducing agent can be incorporatedinto a biodegradable or dissolvable film (or mesh) that is then appliedto the lung. An in situ forming composition can then be sprayed over thefilm, thereby sealing the lung and the film (or mesh) to the desiredlung surface. In a variation of this embodiment, the in situ sealant canbe applied to the lung prior to the application of a biodegradable filmor mesh containing a fibrosis-inducing agent to the treatment area.Exemplary materials for the manufacture of these films or meshes arehyaluronic acid (crosslinked or non-crosslinked), cellulose derivatives(e.g., hydroxypropyl cellulose) and crosslinked poly(ethylene glycol).

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in pulmonary sealants include talc, silk, wool,chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well asanalogues and derivatives of the aforementioned.

As pulmonary sealants are made in a variety of forms, the exact doseadministered can vary with the form. However, certain principles can beapplied in the application of this art. Drug dose can be calculated as afunction of dose per unit area (of the amount of the sealant beingapplied), total drug dose administered can be measured and appropriatesurface concentrations of active drug can be determined. Regardless ofthe method of incorporation of the drug into the pulmonary sealants, theexemplary fibrosing agents, used alone or in combination, should beadministered under the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, the total doseof talc delivered from a pulmonary sealant, or coated onto the surfaceof a lung, should not exceed 100 mg (range of 1 μg to 100 mg). In oneembodiment, the total amount of talc released from the sealant should bein the range of 10 μg to 50 mg. The dose per unit area (i.e., the dosageof talc as a function of the surface area of the lung to which drug isapplied) should fall within the range of 0.05 μg-10 μg per mm² ofsurface area coated. In another embodiment, talc should be applied to alung surface at a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated.In one embodiment, talc is released from the pulmonary sealant such thatfibrosis in the tissue is promoted for a period ranging from severalhours to several months. For example, talc may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of talc (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as talc is administered at half the aboveparameters, a compound half as potent as talc is administered at twicethe above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, the total doseof silk delivered from a pulmonary sealant, or coated onto the surfaceof a lung, should not exceed 100 mg (range of 1 μg to 100 mg). In oneembodiment, the total amount of silk released from the sealant should bein the range of 10 μg to 50 mg. The dose per unit area (i.e., the dosageof silk as a function of the surface area of the lung to which drug isapplied) should fall within the range of 0.05 μg-10 μg per mm² ofsurface area coated. In another embodiment, silk should be applied to alung surface at a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated.As specific (polymeric and non-polymeric) drug delivery vehicles andspecific pulmonary sealants can release silk at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the sealant such that a minimumconcentration of 0.01 nM to 1000 μM of silk is delivered to the tissue.In one embodiment, silk is released from the pulmonary sealant such thatfibrosis in the tissue is promoted for a period ranging from severalhours to several months. For example, silk may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of silk (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as silk is administered at half the aboveparameters, a compound half as potent as silk is administered at twicethe above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, the totaldose of chitosan delivered from a pulmonary sealant, or coated onto thesurface of a lung, should not exceed 100 mg (range of 1 μg to 100 mg).In one embodiment, the total amount of chitosan released from thesealant should be in the range of 10 μg to 50 mg. The dose per unit area(i.e., the dosage of chitosan as a function of the surface area of thelung to which drug is applied) should fall within the range of 0.05μg-10 μg per mm² of surface area coated. In another embodiment, chitosanshould be applied to a lung surface at a dose of 0.05 μg/mm²-10 μg/mm²of surface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific pulmonary sealants can release chitosanat differing rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the sealant such thata minimum concentration of 0.01 nM to 1000 μM of chitosan is deliveredto the tissue. In one embodiment, chitosan is released from thepulmonary sealant such that fibrosis in the tissue is promoted for aperiod ranging from several hours to several months. For example,chitosan may be released in effective concentrations for a periodranging from 1 hour-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of chitosan(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as chitosan is administered at half the above parameters, acompound half as potent as chitosan is administered at twice the aboveparameters, etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, the totaldose of polylysine delivered from a pulmonary sealant, or coated ontothe surface of a lung, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of polylysine released from thesealant should be in the range of 10 μg to 50 mg. The dose per unit area(i.e., the dosage of polylysine as a function of the surface area of thelung to which drug is applied) should fall within the range of 0.05μg-10 μg per mm² of surface area coated. In another embodiment,polylysine should be applied to a lung surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific pulmonary sealantscan release polylysine at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe pulmonary sealant such that a minimum concentration of 0.01 nM to1000 μM of polylysine is delivered to the tissue. In one embodiment,polylysine is released from the pulmonary sealant such that fibrosis inthe tissue is promoted for a period ranging from several hours toseveral months. For example, polylysine may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of polylysine (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as polylysine is administered at halfthe above parameters, a compound half as potent as polylysine isadministered at twice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, the totaldose of fibronectin delivered from a pulmonary sealant, or coated ontothe surface of a lung, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of fibronectin released fromthe sealant should be in the range of 10 μg to 50 mg. The dose per unitarea (i.e., the dosage of fibronectin as a function of the surface areaof the lung to which drug is applied) should fall within the range of0.05 μg-10 μg per mm² of surface area coated. In another embodiment,fibronectin should be applied to a lung surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific pulmonary sealantscan release fibronectin at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe sealant such that a minimum concentration of 0.01 nM to 1000 μM offibronectin is delivered to the tissue. In one embodiment, fibronectinis released from the pulmonary sealant such that fibrosis in the tissueis promoted for a period ranging from several hours to several months.For example, fibronectin may be released in effective concentrations fora period ranging from 1 hour-30 days. It should be readily evident giventhe discussions provided herein that analogues and derivatives offibronectin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as fibronectin is administered at half theabove parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, the totaldose of bleomycin delivered from a pulmonary sealant, or coated onto thesurface of a lung, should not exceed 100 mg (range of 0.01 μg to 100mg). In one embodiment, the total amount of bleomycin released from thesealant should be in the range of 0.10 μg to 50 mg. The dose per unitarea (i.e., the dosage of silk as a function of the surface area of thelung to which drug is applied) should fall within the range of 0.005μg-10 μg per mm² of surface area coated. In another embodiment,bleomycin should be applied to a lung surface at a dose of 0.005μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific pulmonary sealantscan release bleomycin at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe sealant such that a minimum concentration of 0.001 nM to 1000 μM ofbleomycin is delivered to the tissue. In one embodiment, bleomycin isreleased from the pulmonary sealant such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, bleomycin may be released in effective concentrations for aperiod ranging from 1 hour-30 days. It should be readily evident giventhe discussions provided herein that analogues and derivatives ofbleomycin (as described previously) with similar functional activity canbe utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as bleomycin is administered at half the aboveparameters, a compound half as potent as bleomycin is administered attwice the above parameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, the total doseof CTGF delivered from a pulmonary sealant, or coated onto the surfaceof a lung, should not exceed 100 mg (range of 0.01 μg to 100 mg). In oneembodiment, the total amount of CTGF released from the sealant should bein the range of 0.10 μg to 50 mg. The dose per unit area (i.e., thedosage of CTGF as a function of the surface area of the lung to whichdrug is applied) should fall within the range of 0.005 μg-10 μg per mm²of surface area coated. In another embodiment, CTGF should be applied toa lung surface at a dose of 0.005 μg/mm²-10 μg/mm² of surface areacoated. As specific (polymeric and non-polymeric) drug delivery vehiclesand specific pulmonary sealants can release CTGF at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the sealant such that a minimumconcentration of 0.001 nM to 1000 μM of CTGF is delivered to the tissue.In one embodiment, CTGF is released from the pulmonary sealant such thatfibrosis in the tissue is promoted for a period ranging from severalhours to several months. For example, CTGF may be released in effectiveconcentrations for a period ranging from 1 hour-30 days. It should bereadily evident given the discussions provided herein that analogues andderivatives of CTGF (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as CTGF is administered at half the aboveparameters, a compound half as potent as CTGF is administered at twicethe above parameters, etc.).

Optionally, the sealant may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or an analogue orderivative thereof. Inflammatory cytokines are to be used informulations at concentrations that range from 0.0001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the inflammatory cytokine is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.0001μg to 100 mg); preferred 0.001 μg to 50 mg. When used as a devicecoating, the dose is per unit area of 0.0001 μg-500 μg per mm²; with apreferred dose of 0.001 μg/mm²-200 μg/mm². Minimum concentration of10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to be maintained on thedevice surface.

Furthermore, the sealant may alone or additionally comprise an agentthat stimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see, e.g., Example 16). The proliferative agents areto be used in formulations at concentrations that range from 0.0000001to 25 mg/ml depending on the specific clinical application, formulationtype (e.g., gel, liquid, solid, semi-solid), formulation chemistry,duration of required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

14. Hernia Meshes

The present invention provides for the combination of afibrosis-inducing agent and an implantable mesh used to reinforce tissuewall defects such as hernias. Hernias are abnormal protrusions(outpouchings) of an organ or other body structure through a defect ornatural opening in a covering membrane, muscle or bone. Hernias arecommonly caused by activities which result in overstraining (activitiesthat typically increase intra-abdominal pressure), or they can occur asa result of childbirth. Conditions in which a hernia mesh may need to beused include, without limitation, the repair of inguinal (i.e., groin),umbilical, ventral, femoral, abdominal, diaphragmatic, epigastric,gastroesophageal, hiatal, intermuscular, mesenteric, paraperitoneal,rectovaginal, rectocecal, uterine, and vesical hernias.

Inguinal hernias are the most common type of hernias in adults anddevelop as the result of a weakness, tear, gap or opening in the musclewall of the lower abdomen or groin (inguinal canal). As a result, thecontents of the abdomen, such as intestine, may protrude through theopening creating, a bulge and/or pain. Inguinal hernias may becongenital and may become evident with pain or as a bulge at any timeduring life. They can also be acquired as a result of repetitivepressure, strain or injury to the muscles of the abdominal wall.

Umbilical hernias develop in and around the area of the belly button(i.e., navel) and gradually affects those people having a congenitalweakness in the abdominal wall surrounding the umbilicus (the area atwhich the vessels of the fetal umbilical cord exited through the muscleof the abdominal wall). Hernias can occur in this area of weakness atany time from birth through late adulthood. The signs and symptomsinclude pain at or near the navel area as well as the development of anassociated bulge or navel deformity. This bulge pushes out upon the skinbeneath or around the navel, distorting the normal contour andarchitecture in or around the navel.

Incisional or ventral hernias may occur in the area of any priorsurgical incision, and can vary in size from very small, to very largeand complex. They develop as the result of disruption along or adjacentto the area of abdominal wall suturing, often subsequent tension placedon the tissue or other inhibition to adequate healing (infection, poornutrition, obesity, or metabolic diseases). These hernias are present asa bulge or protrusion at or near the area of the prior incision scar.Numerous types of abdominal operations can subsequently develop anincisional hernia at the scar area (e.g., intestinal surgery, vascularsurgery, appendectomy, or laparoscopy).

Femoral hernias, like inguinal hernias develop in the groin area. Thesehernias develop at or very near the leg crease. The defect itself occursin between the inguinal ligament (a tendinous cord that creates the legcrease), the lower side of the pubic bone, and the femoral vein (themajor vein of the leg). This gap is somewhat larger in females due tothe shape and angle of the pelvis, therefore making femoral hernias morecommon in females.

Hernias themselves are not dangerous, but can become extremelyproblematic if they become incarcerated. In an incarcerated hernia, theprotruding viscera are unable to retract back to their normal anatomicallocation and become “trapped” in the hernia sac. If the incarceratedviscera swell, the organ (typically the intestine) can become blocked(causing bowel obstruction) and/or the blood supply to the organ canbecome compromised, this can lead to necrosis and death of theincarcerated portion. As such hernias are often repaired surgically toprevent complications. In its simplest form, the viscera is returned toits normal location and the defect in the wall is primarily closed withsutures, but for bigger gaps, a mesh is placed over the defect to closethe hernia opening. Surgical prostheses used in hernia repair (referredto herein as “hernia meshes”) include prosthetic mesh- or gauze-likematerials, which support the repaired hernia or other body structuresduring the healing process. The addition of a fibrosis-inducing agent tothe implant can encourage the development and ingrowth of strong,fibrous tissue in and around the mesh. This can reinforce the tissue,form scar tissue over the abdominal wall defect and create a lastingrepair that can reduce the incidence of recurrence. For smaller gaps,the fibrosis-inducing agent can be combined with the suture material toproduce the same effect.

In one aspect, the hernia mesh may comprise a biodegradable ornon-biodegradable material. In certain embodiments, the mesh fabric maybe susceptible to the formation of adhesions with the surrounding tissueor organs and/or may promote enhanced tissue ingrowth.

Representative examples of non-biodegradable material for use in herniarepair meshes include the following: tantalum metallic meshes, stainlesssteel meshes, polyamides, polyolefins (e.g., polypropylene andpolyethylene), polyurethanes, polyester/polyether block copolymers,polyesters (PET, polybutyleneterephthalate, andpolyhexyleneterephthalate), polyester cloth (such as DACRON), polyestersheeting (such as MYLAR available from E. 1. DuPont De Nemours andCompany, Wilmington, Del.), nylon meshes, DACRON meshes (such asMERSILENE available from Ethicon, Inc., a Johnson & Johnson Company,Somerville, N.J.), acrylic cloth (ORLON available from E. 1. DuPont DeNemours and Company), polyvinyl sponge (IVALON), polyvinyl cloth(VINYON—N), polypropylene mesh (MARLEX or BARD mesh available from CRBard, Inc., Cranston, R.I.), and PROLENE available from Ethicon, Inc., aJohnson & Johnson Company, Somerville, N.J.), silicones, orfluoropolymers such as fluorinated ethylene propylene (FEP) orpolytetrafluoroethylene (PTFE; such as TEFLON mesh and cloth availablefrom E. 1. DuPont De Nemours and Company (Wilmington, Del.) or expandedPTFE sold under the trade name GORE-TEX available from W.L. Gore &Associates, Inc.).

Hernia repair meshes may comprise a biodegradable or bioresorbablepolymer such as polyglactin (VICRYL; Ethicon, Inc., a Johnson & JohnsonCompany (Somerville, N.J.)), polyglycolic acid (such as DEXON; UnitedStates Surgical/Syneture (Norwalk, Conn.)), carbon fiber mesh,autogenous, heterogenous, and xenogeneic tissue (e.g., pericardium orsmall intestine submucosa), or oxidized, regenerated cellulose.

The surgical mesh used in hernia repairs may be produced by knitting,weaving, braiding, or otherwise forming a plurality of yarns (e.g.,monofilament or multifilament yarns made of polymeric materials such aspolypropylene and polyester) into a support trellis. Mesh fabrics foruse in connection with hernia repairs are disclosed in U.S. Pat. Nos.6,638,284; 5,292,328; 4,769,038 and 2,671,444. Knitted and woven fabricsconstructed from a variety of synthetic fibers and the use of thefabrics, in surgical repair are also discussed in U.S. Pat. Nos.3,054,406; 3,124,136; 4,193,137; 4,347,847; 4,452,245; 4,520,821;4,633,873; 4,652,264; 4,655,221; 4,838,884 and 5,002,551 and EuropeanPatent Application No. 334,046. Implantable hernia meshes are describedin U.S. Pat. Nos. 6,610,006; 6,368,541 and 6,319,264. Hernia meshes forthe repair of hiatal hernias are described in, e.g., U.S. Pat. No.6,436,030. Hernia meshes for the repair of abdominal (e.g., ventral andumbilical) hernias are described in U.S. Pat. No. 6,383,201.Infection-resistant hernia meshes are described in, e.g., U.S. Pat. No.6,375,662. Hernia meshes such as those described in the patents listedabove are suitable for combining with a fibrosis-inducing agent tocreate a mesh which promotes the growth of fibrous tissue.

Commercially available hernia meshes can also be combined with one ormore fibrosis-inducing drugs according to the present invention.Examples of commercially available meshes for use in hernia repair(e.g., inguinal hernias and other hernias of the abdominal wall) thatcan be combined with a fibrosis-inducing agent include: (a) MARLEX orBARD mesh (CR Bard, Inc., Cranston, R.I.)), which is a very denseknitted fabric structure with low porosity; (b) monofilamentpolypropylene mesh such as PROLENE available from Ethicon, Inc., aJohnson & Johnson Company, Somerville, N.J. (see, e.g., U.S. Pat. Nos.5,634,931 and 5,824,082)); (c) SURGISIS GOLD and SURGISIS IHM softtissue graft (both from Cook Surgical, Inc.) which are devicesspecifically configured for use to reinforce soft tissue in repair ofinguinal hernias in open and laparoscopic procedures; (d) thin walledpolypropylene surgical meshes such as are available from Atrium underthe trade names PROLITE, PROLITE ULTRA, and LITEMESH; (e) COMPOSIXhernia mesh (C.R. Bard, Murray Hill, N.J.), which incorporates a meshpatch (the patch includes two layers of an inert synthetic mesh,generally made of polypropylene, and is described in U.S. Pat. No.6,280,453) that includes a filament to stiffen and maintain the devicein a flat configuration; (f) VISILEX mesh (from C.R. Bard), which is apolypropylene mesh that is constructed with monofilament polypropylene;(g) other hernia meshes available from C.R. Bard, Inc. which includePERFIX Plug, KUGEL Hernia Patch, 3D MAX mesh, LHI mesh, DULEX mesh, andthe VENTRALEX Hernia Patch; and (h) other types of polypropylenemonofilament hernia mesh and plug products include HERTRA mesh 1, 2, and2A, HERMESH 3, 4 & 5 and 3-dimensional Plugs T1, T2, and T3 fromHerniamesh USA, Inc (Great Neck, N.Y.). Another implant suitable for usein this embodiment is a prosthetic polypropylene mesh with abioresorbable coating called SEPRAMESH Biosurgical Composite (GenzymeCorporation, Cambridge, Mass.). One side of the mesh is coated with abioresorbable layer of sodium hyaluronate and carboxymethylcellulose,providing a temporary physical barrier that separates the underlyingtissue and organ surfaces from the mesh. The other side of the mesh isuncoated, allowing for complete tissue ingrowth similar to barepolypropylene mesh. In one embodiment, the fibrosis-inducing agent maybe applied only to the uncoated side of SEPRAMESH and not to the sodiumhyaluronate/carboxymethylcellulose coated side.

Other commercially available materials may also be used as herniameshes. Boston Scientific Corporation (Natick, Mass.) sells the TRELEXNATURAL Mesh which is composed of a unique knitted polypropylenematerial. Atrium Medical Corporation (Hudson, N.H.) sells the PROLITEMesh and the PROLITE Ultra Mesh made of thin wall polypropylene and the3-dimensional PROLOOP Plug composed of monofilament loops ofpolypropylene for the treatment of hernia repairs. Ethicon, Inc. makesthe absorbable VICRYL (polyglactin 910) meshes (knitted and woven),PROLENE Polypropylene Hernia Meshes and MERSILENE Polyester Fiber Mesh.Dow Corning Corporation (Midland, Mich.) sells a mesh material formedfrom silicone elastomer known as SILASTIC Rx Medical Grade Sheeting(Platinum Cured). United States Surgical/Syneture (Norwalk, Conn.) sellsa mesh made from absorbable polyglycolic acid under the trade name DEXONMesh Products. Membrana Accurel Systems (Obernburg, Germany) sells theCELGARD microporous polypropylene fiber and membrane. GynecareWorldwide, a division of Ethicon, Inc., a Johnson & Johnson Company(Somerville, N.J.) sells a mesh material made from oxidized, regeneratedcellulose known as INTERCEED TC7.

In one aspect, the present invention provides a hernia repair mesh thatincludes a fibrosis-inducing agent to promote scarring and closure of anabdominal wall defect. The hernia mesh may be coated with the fibrosingagent (with or without a carrier). For example, a fibrosis-inducing drugmay be applied to the surface of the mesh or woven into the fabric.Alternatively, or in addition, the hernia mesh may be composed eitherentirely or partially of fibers that are capable of inducing fibrosis.For example, silk strands or silk can be woven into the hernia mesh orthe hernia mesh can be composed entirely of silk.

In another aspect, the present invention provides a sprayablecomposition that includes a fibrosis-inducing agent that can be used inendoscopic hernia repair procedures to promote scarring and closure ofan abdominal wall defect.

Numerous polymeric and non-polymeric carrier systems described above maybe used in the practice of this embodiment. These compositions canfurther comprise one or more fibrosis-inducing agents to promote theformation of fibrous scar tissue. Methods for incorporating fibrosingcompositions onto or into hernia meshes include: (a) directly affixingto the implant a fibrosing composition (e.g., by either a sprayingprocess or dipping process as described above, with or without acarrier); (b) directly incorporating into the device a fibrosingcomposition (e.g., by either a spraying process or dipping process asdescribed above, with or without a carrier); (c) by coating the devicewith a substance such as a hydrogel which can in turn absorb thefibrosing composition; (d) by interweaving fibrosing composition coatedthread (or the polymer itself formed into a thread) into the devicestructure; (e) by binding a film or mesh which is comprised of, orcoated with, a fibrosing composition to the hernia mesh; (f)constructing the device itself or a portion of the device with afibrosing composition; and/or (g) by covalently binding the fibrosingagent directly to the hernia mesh surface or to a linker (small moleculeor polymer) that is coated or attached to the mesh surface. For herniameshes, the coating process can be performed in such a manner as to (a)coat the exterior surfaces of the mesh, (b) coat the interior surfacesof the mesh, or (c) coat all or parts of both external and internalsurface of the device.

In addition to coating the device with a fibrosis-inducing composition,the fibrosing agent can be mixed with the materials that are used tomake the device such that the fibrosing agent is incorporated into thefinal device.

In addition to (or as an alternative to) applying the fibrosis agent tothe hernia mesh, an in situ forming composition, gel or thermogelcomposition containing a fibrosis-inducing agent can be applied to (as agel, solid implant, liquid or spray) the placement site of the herniamesh, either: (a) prior to placement of the mesh; (b) after placement ofthe hernia mesh; (c) during the placement of the mesh; or (d) anycombination of those three. For the in situ forming thermogel and gelcompositions, the fibrosis-inducing agent(s) (e.g., silk powder,bleomycin) can be incorporated directly into the formulation to producea suspension or a solution or it can be incorporated into a secondarycarrier (e.g., micelles, liposomes, microspheres, microparticles,nanospheres, microparticulates, emulsions and/or microemulsions) that isthen incorporated into the in situ forming compositions. In anotherembodiment, the fibrosis-inducing agent can be electrostatically orcovalently bound to one or more of the polymeric components of thein-situ in situ forming composition.

In a particularly preferred embodiment, the composition may be preparedfrom a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and methylatedcollagen such as described above and contains a fibrosis-inducing agentthat is sprayed onto the surgical site to affix the hernia mesh in placeand induce fibrosis into the mesh.

In another embodiment, the fibrosis-inducing agent can be incorporatedinto a biodegradable or dissolvable film or mesh that is then applied tothe treatment site prior to, or post, implantation of the hernia mesh.Exemplary materials for the manufacture of these films or meshes arehyaluronic acid (crosslinked or non-crosslinked), cellulose derivatives(e.g., hydroxypropyl cellulose), collagen and crosslinked poly(ethyleneglycol).

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in hernia repair meshes include talc, silk,wool, chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well asanalogues and derivatives of the aforementioned.

As hernia meshes and compositions for use with hernia meshes are made ina variety of configurations and sizes, the exact dose administered canvary with mesh size, surface area and design. However, certainprinciples can be applied in the application of this art. Drug dose canbe calculated as a function of dose per unit area (of the portion of themesh being coated), total drug dose administered can be measured andappropriate surface concentrations of active drug can be determined.Regardless of the method of application of the drug to the hernia mesh,the exemplary fibrosing agents, used alone or in combination, should beadministered under the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the hernia mesh, or applied without a polymeric carrier, thetotal dose of talc delivered from a hernia mesh, or coated onto thesurface of a hernia mesh, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of talc released from theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitarea of the implanted mesh (i.e., the dosage of talc as a function ofthe surface area of the portion of the mesh to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, talc should beapplied to a hernia mesh surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. In one embodiment, talc is released from thesurface of a hernia mesh such that fibrosis in the tissue is promotedfor a period ranging from several hours to several months. For example,talc may be released in effective concentrations for a period rangingfrom 1 week to 9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of talc (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent astalc is administered at half the above parameters, a compound half aspotent as talc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the hernia mesh, or applied without a polymeric carrier, thetotal dose of silk delivered from a hernia mesh, or coated onto thesurface of a hernia mesh, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of silk released from thehernia mesh should be in the range of 10 μg to 50 mg. The dose per unitarea of the implanted mesh (i.e., the dosage of silk as a function ofthe surface area of the portion of the mesh to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, silk should beapplied to a hernia mesh surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific hernia meshes can release silk atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the hernia mesh suchthat a minimum concentration of 0.01 nM to 1000 μM of silk is deliveredto the tissue. In one embodiment, silk is released from the surface of ahernia mesh such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, silk may bereleased in effective concentrations for a period ranging from 1 week-9months. It should be readily evident given the discussions providedherein that analogues and derivatives of silk (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as silk isadministered at half the above parameters, a compound half as potent assilk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the hernia mesh, or applied without a polymeric carrier, thetotal dose of chitosan delivered from a hernia mesh, or coated onto thesurface of a hernia mesh, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of chitosan released from thehernia mesh should be in the range of 10 μg to 50 mg. The dose per unitarea of the implanted mesh (i.e., the dosage of chitosan as a functionof the surface area of the portion of the mesh to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm² of surface area coated. In another embodiment, chitosan should beapplied to a hernia mesh surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific hernia meshes can release chitosan atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the hernia mesh suchthat a minimum concentration of 0.01 nM to 1000 μM of chitosan isdelivered to the tissue. In one embodiment, chitosan is released fromthe surface of a hernia mesh such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, chitosan may be released in effective concentrations for aperiod ranging from 1 week to 9 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofchitosan (as described previously) with similar functional activity canbe utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as chitosan is administered at half the aboveparameters, a compound half as potent as chitosan is administered attwice the above parameters, etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the hernia mesh, or applied without a polymeric carrier, thetotal dose of polylysine delivered from a hernia mesh, or coated ontothe surface of a hernia mesh, should not exceed 100 mg (range of 1 μg to100 mg). In one embodiment, the total amount of polylysine released fromthe hernia mesh should be in the range of 10 μg to 50 mg. The dose perunit area of the implanted mesh (i.e., the dosage of polylysine as afunction of the surface area of the portion of the mesh to which drug isapplied and/or incorporated) should fall within the range of 0.05 μg-10μg per mm² of surface area coated. In another embodiment, polylysineshould be applied to a hernia mesh surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific hernia meshes can release polylysineat differing rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the hernia mesh suchthat a minimum concentration of 0.01 nM to 1000 μM of polylysine isdelivered to the tissue. In one embodiment, polylysine is released fromthe surface of a hernia mesh such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, polylysine may be released in effective concentrations for aperiod ranging from 1 week to 9 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofpolylysine (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as polylysine is administered at half the aboveparameters, a compound half as potent as polylysine is administered attwice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the hernia mesh, or applied without a polymeric carrier,the total dose of fibronectin delivered from a hernia mesh, or coatedonto the surface of a hernia mesh, should not exceed 100 mg (range of 1μg to 100 mg). In one embodiment, the total amount of fibronectinreleased from the hernia mesh should be in the range of 10 μg to 50 mg.The dose per unit area of the implanted mesh (i.e., the dosage offibronectin as a function of the surface area of the portion of the meshto which drug is applied and/or incorporated) should fall within therange of 0.05 μg-10 μg per mm² of surface area coated. In anotherembodiment, fibronectin should be applied to a hernia mesh surface at adose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specific herniameshes can release fibronectin at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the hernia mesh such that a minimum concentration of 0.01nM to 1000 μM of fibronectin is delivered to the tissue. In oneembodiment, fibronectin is released from the surface of a hernia meshsuch that fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, fibronectin may bereleased in effective concentrations for a period ranging from 1 week to9 months. It should be readily evident given the discussions providedherein that analogues and derivatives of fibronectin (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asfibronectin is administered at half the above parameters, a compoundhalf as potent as fibronectin is administered at twice the aboveparameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the hernia mesh, or applied without a polymeric carrier, thetotal dose of bleomycin delivered from a hernia mesh, or coated onto thesurface of a hernia mesh, should not exceed 100 mg (range of 0.01 μg to100 mg). In one embodiment, the total amount of bleomycin released fromthe hernia mesh should be in the range of 0.10 μg to 50 mg. The dose perunit area of the implanted mesh (i.e., the dosage of bleomycin as afunction of the surface area of the portion of the mesh to which drug isapplied and/or incorporated) should fall within the range of 0.005 μg-10μg per mm² of surface area coated. In another embodiment, bleomycinshould be applied to a hernia mesh surface at a dose of 0.005 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific hernia meshes can release bleomycinat differing rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the hernia mesh suchthat a minimum concentration of 0.001 nM to 1000 μM of bleomycin isdelivered to the tissue. In one embodiment, bleomycin is released fromthe surface of a hernia mesh such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, bleomycin may be released in effective concentrations for aperiod ranging from 1 week to 9 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofbleomycin (as described previously) with similar functional activity canbe utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as bleomycin is administered at half the aboveparameters, a compound half as potent as bleomycin is administered attwice the above parameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the hernia mesh, or applied without a polymeric carrier, thetotal dose of CTGF delivered from a hernia mesh, or coated onto thesurface of a hernia mesh, should not exceed 100 mg (range of 0.01 μg to100 mg). In one embodiment, the total amount of CTGF released from thehernia mesh should be in the range of 0.10 μg to 50 mg. The dose perunit area of the implanted mesh (i.e., the dosage of CTGF as a functionof the surface area of the portion of the mesh to which drug is appliedand/or incorporated) should fall within the range of 0.005 μg-10 μg permm² of surface area coated. In another embodiment, CTGF should beapplied to a hernia mesh surface at a dose of 0.005 μg/mm²-10 μg/mm² ofsurface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific hernia meshes can release CTGF atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the hernia mesh suchthat a minimum concentration of 0.001 nM to 1000 μM of CTGF is deliveredto the tissue. In one embodiment, CTGF is released from the surface of ahernia mesh such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, CTGF may bereleased in effective concentrations for a period ranging from 1 week to9 months. It should be readily evident given the discussions providedherein that analogues and derivatives of CTGF (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as CTGF isadministered at half the above parameters, a compound half as potent asCTGF is administered at twice the above parameters, etc.).

Optionally, the device or composition may alone or additionally comprisean inflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF,GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or ananalogue or derivative thereof. Inflammatory cytokines are to be used informulations at concentrations that range from 0.0001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the inflammatory cytokine is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.0001μg to 100 mg); preferred 0.001 μg to 50 mg. When used as a devicecoating, the dose is per unit area of 0.0001 μg-500 μg per mm²; with apreferred dose of 0.001 μg/mm²-200 μg/mm². Minimum concentration of10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to be maintained on thedevice surface.

Furthermore, the device or composition may alone or additionallycomprise an agent that stimulates cellular proliferation. Examplesinclude: dexamethasone, isotretinoin (13-cis retinoic acid),17-β-estradiol, estradiol, 1-a-25 dihydroxyvitamin D₃,diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid(ATRA), and analogues and derivatives thereof. Doses used are thoseconcentrations which are demonstrated to stimulate cell proliferation(see, e.g., Example 16). The proliferative agents are to be used informulations at concentrations that range from 0.1 ng/ml to 25 mg/mldepending on the specific clinical application, formulation type (e.g.,gel, liquid, solid, semi-solid), formulation chemistry, duration ofrequired application, type of medical device interface and formulationvolume and or surface area coverage required. Preferably, theproliferative agent is released in effective concentrations for a periodranging from 1-180 days. The total dose for a single application istypically not to exceed 500 mg (range of 0.0001 μg to 200 mg); preferred0.001 μg to 100 mg. When used as a device coating, the dose is per unitarea of 0.00001 μg-500 μg per mm²; with a preferred dose of 0.0001μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

15. Shoulder Capsule, Ligament and Tendon Repairs

In one aspect, the present invention provides compositions and devicesfor use in shoulder capsule, ligament, and tendon repair surgeries. Theterm “ligament” refers to a band of fibrous connective tissue thatconnects bones to cartilage, which serves to support and strengthen ajoint. The term “tendon” refers to a fibrous cord of connective tissuein which the fibers of a muscle end and by which the muscle is attachedto a bone or other structure. Over 700,000 ligament and tendon repairsare performed annually in the United States including: repairs of thefoot and ankle (11% of the total; particularly the Achilles tendon, butalso the peroneal tendons, plantar fascia repair, extensor digitorumtendons, anterior tibial tendon, lateral stabilizing ligaments of theankle, anterior inferior tibial fibular ligament, medial deltoidligament), knee (38% of the total; particularly the medial collateralligament, lateral collateral ligament, anterior cruciate ligament,posterior cruciate ligament, and meniscal repair, but also chondralsurface repair, patellar tendon repair, bicep femoris tendon repair),hip (rectus femoris origin, gracilis tendon, avulsion of the hamstringmuscle origins), pelvis (gracilis muscle origin, adductor muscleorigins, rectus femoris insertion, pubic symphysis cartilage), shoulder(25% of the total; particularly the rotator cuff tendons; alsoacromioclavicular stabilizing ligaments, biceps tendons), back(sacroiliac stabilizing ligaments), elbow (biceps tendons, lateralepicondyle—extensor origins, medial epicondyle—flexor origins, tricepscomplex), and hand (26% of the total; flexor and extensor tendons of thewrist and hand). The addition of a fibrosis-inducing agent to a softtissue repair procedure (such as those listed above) can increasescarring and lead to a more durable, sustainable and functional outcomefor the patient.

Several collagen-based surgical meshes have been produced to function astissue repair products for use during open surgery and are suitable forthe delivery of a fibrosis-inducing agent. For example, collagensurgical patches, such as the FORTAFLEX Patch (Organogenesis Inc.,Canton, Mass.), are used in tendon, ligament and cartilage repairsurgeries to reinforce the tissue during surgical repair and healing.Tendon and ligament repair surgeries typically involve the use of sutureanchors or suture-passing devices to secure the damaged tendons to thebone. Depending on the size of the tear, a collagen patch may be used tofill a defect in the tendon or ligament. The collagen implant serves asa resorbable scaffold that provides biomechanical strength, support andreinforcement of soft tissues that are surgically repaired. Eventuallythe collagen becomes infiltrated and replaced by host tissue cells(primarily fibroblasts) which are able to repair and regenerate thedamaged tissue (primarily organized connective tissue).

Unfortunately, for many of these surgical interventions, durability ofthe collagen implant becomes an important clinical issue. In tendon andligament repairs, it is desirable for the collagen implant to providestructural integrity until full healing and native tissue replacementcan occur. In the case of large tissue defects, which can take severalmonths to over a year to heal, limited durability of the collagenimplant can become a clinical problem if it completely absorbs prior tothe completion of healing. In an attempt to address this problem,manufacturers have sought to produce a collagen implant with improveddurability through by increasing the amount crosslinking between thecollagen fibers. However highly crosslinked collagen material hasdifferent scaffolding and degradation profiles than native collagen anddoes not function optimally in the healing process. The addition of oneor more fibrosis-inducing agents to a collagen patch has severalimportant clinical implications. First, since it does not requirealteration of the collagen material itself, the collagen scaffoldremains in its native state and is able to support the normal ingrowthof reparative fibrous connective tissue. Secondly, the fibrosis-inducingagent stimulates the ingrowth of the body's own fibrous connectivetissue, speeding the healing process and allowing repair to occur priorto failure of the implant. The result is a more rapid, stronger,longer-lasting repair composed of the body's own connective tissue whichleads to a better clinical outcome and a lower risk of failure.

In one aspect, the present invention provides compositions and devicesthat include a fibrosis-inducing agent, where the agent may encouragescar formation to strengthen the surgically repaired ligament (e.g.,anterior or posterior cruciate ligament), tendon (e.g., Achillestendon), or joint capsule (e.g., the anterior capsule to preventrecurrent shoulder dislocation). A variety of embodiments are suitablefor the practice of this invention, including delivering to the softtissue operative site: (1) a “thermopaste” containing afibrosis-inducing agent that is applied to a desired site as a fluid,and hardens to a solid of the desired shape at a specified temperature(e.g., body temperature); (2) as a spray (i.e., “nanospray”) containinga fibrosis-inducing agent that can be delivered to a desired site eitherdirectly in open surgery, or through a specialized surgical apparatus(e.g., an endoscope), and which subsequently hardens to a solid thatadheres to the tissue it is applied to; (3) as an adherent, pliable,resilient, polymer film containing a fibrosis-inducing agent applied toa desired site either directly or through a specialized apparatus, andwhich preferably adheres to the site to which it is applied; and/or (4)as a fluid composed of a suspension of microspheres containing afibrosis-inducing agent in an appropriate carrier medium, which isapplied to a desired site either directly or via a specializedapparatus, and which leaves a layer of microspheres at the applicationsite. Representative examples of each of the above embodiments are setforth in more detail below.

In another embodiment, tendons, ligaments or the shoulder capsule can betreated with a fibrosis-inducing agent combined with a composition thatforms a gel in situ. These can be crosslinked gels, thermogels, ortraditional gel compositions. For the in situ forming gels, thermogeland gel compositions, the fibrosis-inducing agent(s) can be incorporateddirectly into the formulation to produce a suspension or a solution(e.g., silk powder, bleomycin) or it can be incorporated into asecondary carrier (e.g., micelles, liposomes, microspheres,microparticles, nanospheres, microparticulates, emulsions and/ormicromulsions) that is then incorporated into the in situ forming gelcompositions. In certain embodiments, the fibrosis-inducing agent can beelectrostatically or covalently bound to one or more of the polymericcomponents of the in situ forming gel composition.

In yet another embodiment, the fibrosis-inducing agent can beincorporated into a biodegradable or dissolvable film or mesh that isthen applied to the treatment site prior to, during, or post treatment.The film or mesh can be applied to the entire treatment site, used tobridge or fill tissue defects, or they can be applied as a patch to avery specific location within the treatment site. Preferred materialsfor the manufacture of these films or meshes are hyaluronic acid(crosslinked or non-crosslinked), cellulose derivatives (e.g.,hydroxypropyl cellulose), collagen and crosslinked poly(ethyleneglycol).

In yet another embodiment, the fibrosis-inducing agent can be in aninjectable or sprayable form (particularly useful for endoscopicdelivery) that can be delivered directly into the treatment site,applied over the surgically repaired tendon, ligament or capsule, usedto patch tissue defects, or applied to the tissue surrounding thetreatment site. The compositions may be readily applied as a “spray”,which subsequently solidifies into a film or coating. A sprayableformulation of a fibrosing agent may be used in, for example, kneesurgery (e.g., MCL and ACL) repairs to reinforce the ligament or inankle surgery to reinforce a tendon (e.g., Achilles' tendon). Thecompositions also may be used for cosmetic purposes, such as,reinforcement or augmentation of the Cooper's ligament (e.g., forsupport or lifting of the breast). For example, the ligament may becoated with a scarring fibrosing agent in order to cause the ligament tocontract (i.e., shorten) and lift the breast tissue. Thefibrosis-inducing agent(s) (e.g., silk powder, bleomycin) can beincorporated directly into the formulation to produce a suspension or asolution or incorporated into a secondary carrier (e.g., micelles,liposomes, microspheres, microparticles, nanospheres, microparticulates,emulsions and/or micromulsions) that is then incorporated into theinjectable or sprayable composition. The spray, which includes a tissueadherent polymer containing a fibrosis-inducing agent, may be preparedfrom microspheres of a wide array of sizes. In another embodiment, thefibrosis-inducing agent can be electrostatically or covalently bound toone or more of the polymeric components of the injectable or sprayablecomposition.

The injectable and sprayable compositions can further comprise a polymerto enhance the viscosity of the solution. Polymers that can be used forthis purpose include hyaluronic acid, CMC, PLURONICS, such as PLURONICF127, and gels (including thermo gels) of the form X—Y, X—Y—X, or Y—X—Y(where X is a degradable polyester and Y is a polyalkylene oxide,preferably polyethylene glycol or the mono-methyl ether thereof). Inanother embodiment, the injectable or sprayable formulation can furthercomprise one or more biocompatible solvents. These can include ethanol,DMSO, NMP, poly(ethylene glycol)-200, and/or poly(ethylene glycol)-300.

One material that is of particular interest for the practice of thisembodiment is prepared from a 4-armed thiol PEG (10K), a 4-armed NHSPEG(10K) and methylated collagen such as described above. In oneembodiment, a material made from 4-armed thiol PEG (10K), a 4-armed NHSPEG(10K) and methylated collagen is loaded with a fibrosis-inducingagent and sprayed (directly or via endoscope) directly onto thetreatment site, used to patch a tissue defect, applied to the tissuesurrounding the treatment site, or applied over a damaged tendon,ligament or capsule to adhere the tissues together and induce fibrosis.

It should be apparent to one of skill in the art that potentially anyfibrosis-inducing agents described above may be utilized alone, or incombination, in the practice of this embodiment. Exemplary fibrosingagents for use in capsule, ligament, and tendon repair devices andimplants include talc, silk, wool, chitosan, polylysine, fibronectin,bleomycin, and CTGF, as well as analogues and derivatives of theaforementioned.

As shoulder capsule, ligament, and tendon repair devices andcompositions are made in a variety of configurations and sizes dependingupon the location and the degree of the injury, the exact doseadministered can vary with implant size, surface area and design.However, certain principles can be applied in the application of thisart. Drug dose can be calculated as a function of dose per unit area (orvolume) of the implant, total drug dose administered can be measured andappropriate surface concentrations of active drug can be determined.Regardless of the method of application of the drug to the jointcapsule, ligament, or tendon repair device or implant, the exemplaryfibrosing agents, used alone or in combination, should be administeredunder the following dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of talc delivered from a joint capsule, ligament, ortendon repair implant, or coated onto the surface of a joint capsule,ligament, or tendon repair implant, should not exceed 100 mg (range of 1μg to 100 mg). In one embodiment, the total amount of talc released fromthe implant should be in the range of 10 μg to 50 mg. The dose per unitvolume of the implant (i.e., the dosage of talc as a function of thevolume of the portion of the implant to which drug is applied and/orincorporated) should fall within the range of 0.05 μg-10 μg per mm³ ofmaterial implanted. In another embodiment, talc should be applied to ajoint capsule, ligament, or tendon repair implant surface at a dose of0.05 μg/mm²-10 μg/mm² of surface area coated. In one embodiment, talc isreleased from the surface of a joint capsule, ligament, or tendon repairimplant such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, talc may bereleased in effective concentrations for a period ranging from 1 to 12months. It should be readily evident given the discussions providedherein that analogues and derivatives of talc (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as talc isadministered at half the above parameters, a compound half as potent astalc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of silk delivered from a joint capsule, ligament, ortendon repair implant, or coated onto the surface of a joint capsule,ligament, or tendon repair implant, should not exceed 100 mg (range of 1μg to 100 mg). In one embodiment, the total amount of silk released fromthe implant should be in the range of 10 μg to 50 mg. The dose per unitvolume of the implant (i.e., the dosage of silk as a function of thevolume of the portion of the implant to which drug is applied and/orincorporated) should fall within the range of 0.05 μg-10 μg per mm³ ofmaterial implanted. In another embodiment, silk should be applied to ajoint capsule, ligament, or tendon repair implant surface at a dose of0.05 μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific medical implants canrelease silk at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from the jointcapsule, ligament, or tendon repair implant such that a minimumconcentration of 0.01 nM to 1000 μM of silk is delivered to the tissue.In one embodiment, silk is released from the surface of a joint capsule,ligament, or tendon repair implant such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, silk may be released in effective concentrations for a periodranging from 1 to 12 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of silk (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent assilk is administered at half the above parameters, a compound half aspotent as silk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of chitosan delivered from a joint capsule, ligament, ortendon repair implant, or coated onto the surface of a joint capsule,ligament, or tendon repair implant, should not exceed 100 mg (range of 1μg to 100 mg). In one embodiment, the total amount of chitosan releasedfrom the implant should be in the range of 10 μg to 50 mg. The dose perunit volume of the implant (i.e., the dosage of chitosan as a functionof the volume of the portion of the implant to which drug is appliedand/or incorporated) should fall within the range of 0.05 μg-10 μg permm³ of material implanted. In another embodiment, chitosan should beapplied to a joint capsule, ligament, or tendon repair implant surfaceat a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificmedical implants can release chitosan at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the joint capsule, ligament, or tendon repairimplant such that a minimum concentration of 0.01 nM to 1000 μM ofchitosan is delivered to the tissue. In one embodiment, chitosan isreleased from the surface of a joint capsule, ligament, or tendon repairimplant such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, chitosan maybe released in effective concentrations for a period ranging from 1 to12 months. It should be readily evident given the discussions providedherein that analogues and derivatives of chitosan (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent aschitosan is administered at half the above parameters, a compound halfas potent as chitosan is administered at twice the above parameters,etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of polylysine delivered from a joint capsule, ligament,or tendon repair implant, or coated onto the surface of a joint capsule,ligament, or tendon repair implant, should not exceed 100 mg (range of 1μg to 100 mg). In one embodiment, the total amount of polylysinereleased from the implant should be in the range of 10 μg to 50 mg. Thedose per unit volume of the implant (i.e., the dosage of polylysine as afunction of the volume of the portion of the implant to which drug isapplied and/or incorporated) should fall within the range of 0.05 μg-10μg per mm³ of material implanted. In another embodiment, polylysineshould be applied to a joint capsule, ligament, or tendon repair implantsurface at a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. Asspecific (polymeric and non-polymeric) drug delivery vehicles andspecific medical implants can release polylysine at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the joint capsule, ligament, or tendonrepair implant such that a minimum concentration of 0.01 nM to 1000 μMof polylysine is delivered to the tissue. In one embodiment, polylysineis released from the surface of a joint capsule, ligament, or tendonrepair implant such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, polylysinemay be released in effective concentrations for a period ranging from 1to 12 months. It should be readily evident given the discussionsprovided herein that analogues and derivatives of polylysine (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent aspolylysine is administered at half the above parameters, a compound halfas potent as polylysine is administered at twice the above parameters,etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the device or implant, or applied without a polymericcarrier, the total dose of fibronectin delivered from a joint capsule,ligament, or tendon repair implant, or coated onto the surface of ajoint capsule, ligament, or tendon repair implant, should not exceed 100mg (range of 1 μg to 100 mg). In one embodiment, the total amount offibronectin released from the implant should be in the range of 10 μg to50 mg. The dose per unit volume of the implant (i.e., the dosage offibronectin as a function of the volume of the portion of the implant towhich drug is applied and/or incorporated) should fall within the rangeof 0.05 μg-10 μg per mm³ of material implanted. In another embodiment,fibronectin should be applied to a joint capsule, ligament, or tendonrepair implant surface at a dose of 0.05 μg/mm²-10 μg/mm² of surfacearea coated. As specific (polymeric and non-polymeric) drug deliveryvehicles and specific medical implants can release fibronectin atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the joint capsule,ligament, or tendon repair implant such that a minimum concentration of0.01 nM to 1000 μM of fibronectin is delivered to the tissue. In oneembodiment, fibronectin is released from the surface of a joint capsule,ligament, or tendon repair implant such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, fibronectin may be released in effective concentrations for aperiod ranging from 1 to 12 months. It should be readily evident giventhe discussions provided herein that analogues and derivatives offibronectin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as fibronectin is administered at half theabove parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of bleomycin delivered from a joint capsule, ligament, ortendon repair implant, or coated onto the surface of a joint capsule,ligament, or tendon repair implant, should not exceed 100 mg (range of0.01 μg to 100 mg). In one embodiment, the total amount of bleomycinreleased from the implant should be in the range of 0.10 μg to 50 mg.The dose per unit volume of the implant (i.e., the dosage of bleomycinas a function of the volume of the portion of the implant to which drugis applied and/or incorporated) should fall within the range of 0.005μg-10 μg per mm³ of material implanted. In another embodiment, bleomycinshould be applied to a joint capsule, ligament, or tendon repair implantsurface at a dose of 0.005 μg/mm²-10 μg/mm² of surface area coated. Asspecific (polymeric and non-polymeric) drug delivery vehicles andspecific medical implants can release bleomycin at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the joint capsule, ligament, or tendonrepair implant such that a minimum concentration of 0.001 nM to 1000 μMof bleomycin is delivered to the tissue. In one embodiment, bleomycin isreleased from the surface of a joint capsule, ligament, or tendon repairimplant such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, bleomycin maybe released in effective concentrations for a period ranging from 1 to12 months. It should be readily evident given the discussions providedherein that analogues and derivatives of bleomycin (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asbleomycin is administered at half the above parameters, a compound halfas potent as bleomycin is administered at twice the above parameters,etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the device or implant, or applied without a polymeric carrier,the total dose of CTGF delivered from a joint capsule, ligament, ortendon repair implant, or coated onto the surface of a joint capsule,ligament, or tendon repair implant, should not exceed 100 mg (range of0.01 μg to 100 mg). In one embodiment, the total amount of CTGF releasedfrom the implant should be in the range of 0.10 μg to 50 mg. The doseper unit volume of the implant (i.e., the dosage of CTGF as a functionof the volume of the portion of the implant to which drug is appliedand/or incorporated) should fall within the range of 0.005 μg-10 μg permm³ of material implanted. In another embodiment, CTGF should be appliedto a joint capsule, ligament, or tendon repair implant surface at a doseof 0.005 μg/mm²-10 μg/mm² of surface area coated. As specific (polymericand non-polymeric) drug delivery vehicles and specific medical implantscan release CTGF at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from thejoint capsule, ligament, or tendon repair implant such that a minimumconcentration of 0.001 nM to 1000 μM of CTGF is delivered to the tissue.In one embodiment, CTGF is released from the surface of a joint capsule,ligament, or tendon repair implant such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, CTGF may be released in effective concentrations for a periodranging from 1 to 12 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of CTGF (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asCTGF is administered at half the above parameters, a compound half aspotent as CTGF is administered at twice the above parameters, etc.).

Optionally, the device may alone or additionally comprise aninflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or a bonemorphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof).

Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, orBMP-7 or an analogue or derivative thereof) are to be used informulations at concentrations that range from 0.001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the bone morphogenic protein is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.001μg to 500 mg); preferred 1 μg to 250 mg. When used as a device coating,the dose is per unit area of 0.001 μg-1000 μg per mm²; with a preferreddose of 0.01 μg/mm²-200 μg/mm². Minimum concentration of 10⁻⁹-10⁴ M ofbone morphogenic protein is to be maintained on the device surface.

Inflammatory cytokines are to be used in formulations at concentrationsthat range from 0.0001 μg/ml to approximately 20 mg/ml depending on thespecific clinical application, formulation type (e.g., gel, liquid,solid, semi-solid), formulation chemistry, duration of requiredapplication, type of medical device interface and formulation volume andor surface area coverage required. Preferably, the inflammatory cytokineis released in effective concentrations for a period ranging from 1-180days. The total dose for a single application is typically not to exceed500 mg (range of 0.0001 μg to 100 mg); preferred 0.001 μg to 50 mg. Whenused as a device coating, the dose is per unit area of 0.0001 μg-500 μgper mm²; with a preferred dose of 0.001 μg/mm²-200 μg/mm². Minimumconcentration of 10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to bemaintained on the device surface.

Furthermore, the device may alone or additionally comprise an agent thatstimulates cellular proliferation. Examples include: dexamethasone,isotretinoin (13-cis retinoic acid), 17-β-estradiol, estradiol, 1-a-25dihydroxyvitamin D₃, diethylstibesterol, cyclosporine A, L-NAME,all-trans retinoic acid (ATRA), and analogues and derivatives thereof.Doses used are those concentrations which are demonstrated to stimulatecell proliferation (see, e.g., Example 16). The proliferative agents areto be used in formulations at concentrations that range from 0.0000001to 25 mg/ml depending on the specific clinical application, formulationtype (e.g., gel, liquid, solid, semi-solid), formulation chemistry,duration of required application, type of medical device interface andformulation volume and or surface area coverage required. Preferably,the proliferative agent is released in effective concentrations for aperiod ranging from 1-180 days. The total dose for a single applicationis typically not to exceed 500 mg (range of 0.0001 μg to 200 mg);preferred 0.001 μg to 100 mg. When used as a device coating, the dose isper unit area of 0.00001 μg-500 μg per mm²; with a preferred dose of0.0001 μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

16. Septal Occlusion Patches

The present invention provides for the combination of afibrosis-inducing agent and a septal occlusion patch. Incorporation of afibrosing agent into or onto a septal occlusion patch can promote tissuegrowth that will anchor the device to the septum and provide a betterseal, thus reducing the incidence of leaks.

Approximately half of congenital cardiovascular defects let blood flowbetween the right and left chambers of the heart. The two most commontypes of defects are atrial septal defects involving an opening in thewall between the two atria and ventricular septal defects involving anopening in the wall between the ventricles. Other similar cardiacdefects are patent foramen ovale and patent ductus arteriosus. In theUnited States alone, about 20,000 babies are born each year with one ofthese malformations. In addition approximately 1 million Americans withcongenital cardiovascular defects are alive today and will developcomplications, such as pulmonary hypertension, congestive heart failure,atrial arrhythmia, impaired aerobic capacity and stroke, which willrequire treatment.

Transcatheter closure of cardiac defects is becoming an attractivealternative to surgical closure because it reduces the risks andmorbidity inherent to cardiac surgery. Several transcatheter techniquesand septal occlusion devices have been developed and are usedclinically. The latest generation of devices is composed of two disksjoined by a center stalk. The stalk occludes the defect and the disksadhere to each side of the wall. The collapsed device is positioned viaa catheter and released under fluoroscopy guidance. The size of thesedevices, however, limits the use of this technology in small patients.Further, patients with large defects and patients having an insufficientseptal rim around the defect typically cannot be treated with septalocclusion devices. In addition, adverse complications associated withseptal occlusion devices include incomplete closure (leaks), frictionlesions and cardiac perforation.

The addition of a fibrosis-inducing agent to the implant can encouragethe development and ingrowth of strong, fibrous tissue in and around theseptal occlusion device. This can reinforce the tissue, form scar tissueover the implant and create a lasting repair. Tissue growth can anchorthe device to the septum and provide an improved seal, thus minimizingthe occurrence of leaks. Further, incorporation of the device by cardiactissue can prevent friction fracture and cardiac perforation. Tissuegrowth in and/or on the device can strengthen the device and allow theuse of thinner devices, thus reducing bulkiness and allowing inclusionof a wider patient population. Increased strength of the device can alsoallow for the treatment of larger defects. Finally, patients having asmall septal rim that generally would be insufficient for transcathetertreatment will become eligible for this procedure because tissue growthwill anchor the device in place.

The term septal occlusion patches refer to devices that are designed tobe placed within or near the vasculature of the host to block the flowof blood through a vascular defect. Examples of septal occlusion patchesinclude, without limitation, defect closure devices, shunt closureapparatus, intracardiac occluders, occluding disks, defect occludingsystems, and intravascular shunt devices.

Septal occlusion patches may be composed of a variety of configurations.For example, the septal occlusion patch may center itself elasticallyagainst a margin of an opening by being shaped to form a closed loopwith at least two spaced apart windings. See e.g., U.S. Pat. No.6,355,052. The septal occlusion patch may be composed of a deliveryshaft and a patch releasably held at the distal end whereby the patchhas a collapsed configuration for positioning through the lumen of asleeve and a deployment configuration for positioning across a septaldefect. See e.g., U.S. Pat. No. 6,346,074. The septal occlusion patchmay be composed of two flexible membranes having an elasticallydeformable frame extending along the periphery to allow the membranes tocollapse for passage through a catheter while returning to theirpredetermined shape following implantation. See e.g., U.S. Pat. Nos.6,077,291 and 5,334,217. The septal occlusion patch may be composed ofan occlusion bag with two sacs connected to each other and an unattachedsuper-elastic wire frame having two sets of multiple loops containedwithin the occlusion bag. See e.g., U.S. Pat. No. 5,861,003. The septalocclusion patch may be composed of at least two clips with fasteningmeans that firmly grip the peripheral portions of the opening as well asa flat fabric occluder which is used to close the opening of the septum.See e.g., U.S. Pat. No. 5,507,811. The septal occlusion patch may becomposed of two occluders connected by a fastener with a pivot forallowing rotation of the occluders when in an expanded configuration.See e.g., U.S. Pat. No. 5,451,235. The septal occlusion patch may becomposed of two foldable foam resin or polyurethane discs with suturedwire skeletons whereby the discs are secured to each other using abuttoning technique through the heart defect. See e.g., U.S. Pat. Nos.5,433,727; 5,284,488 and 4,917,089. The septal occlusion patch may be anumbrella-like expansive device composed of a plurality of struts movablymounted on a hub such that the patch has a first collapsed position anda second expanded position. See e.g., U.S. Pat. No. 4,007,743. Theseptal occlusion patch may be composed of a mechanical expansion meansthat has a dual set of umbrella-like structures with a central hub forplacement on opposite sides of the shunt defect. See e.g., U.S. Pat. No.3,874,388.

Commercially available septal occlusion patches can also be combinedwith one or more fibrosis-inducing drugs according to the presentinvention. For example, W. L. Gore and Associates, Inc. (Newark, Del.)sells its HELEX Septal Occluder which is used as a minimally invasiveclosure of atrial septal defects. NMT Medical, Inc. (Boston, Mass.)sells their CARDIOSEAL and STARFLEX which are designed for minimallyinvasive procedures. AGA Medical Corp. (Golden Valley, Minn.) sellstheir AMPLATZER Septal Occluder.

In one aspect, the present invention provides a septal occlusion patchthat includes a fibrosis-inducing agent to promote scarring and closureof a cardiac defect. The septal occlusion patch may be coated with thefibrosing agent (with or without a carrier). For example, afibrosis-inducing drug may be applied to the surface of the patch orwoven into the fabric. Alternatively, or in addition, the septalocclusion patch may be composed either entirely or partially of fibersthat are capable of inducing fibrosis. For example, silk strands or silkcan be woven into the septal occlusion patch or the septal occlusionpatch can be composed entirely of silk.

In another aspect, the present invention provides a sprayablecomposition that includes a fibrosis-inducing agent that can be used intranscatheter repair procedures to promote scarring and closure of acardiac defect.

Numerous polymeric and non-polymeric carrier systems described above maybe used in the practice of this embodiment. These compositions canfurther comprise one or more fibrosis-inducing agents to promote theformation of fibrous scar tissue. Methods for incorporating fibrosingcompositions onto or into septal occlusion patch include: (a) directlyaffixing to the implant a fibrosing composition (e.g., by either aspraying process or dipping process as described above, with or withouta carrier); (b) directly incorporating into the device a fibrosingcomposition (e.g., by either a spraying process or dipping process asdescribed above, with or without a carrier); (c) by coating the devicewith a substance such as a hydrogel which can in turn absorb thefibrosing composition; (d) by interweaving fibrosing composition coatedthread (or the polymer itself formed into a thread) into the devicestructure; (e) by binding a film or mesh which is comprised of, orcoated with, a fibrosing composition to the septal occlusion patch; (f)constructing the device itself or a portion of the device with afibrosing composition; and/or (g) by covalently binding the fibrosingagent directly to the septal occlusion patch surface or to a linker(small molecule or polymer) that is coated or attached to the patchsurface. For septal occlusion patch, the coating process can beperformed in such a manner as to (a) coat the exterior surfaces of thepatch, (b) coat the interior surfaces of the patch, or (c) coat all orparts of both external and internal surface of the patch.

In addition to coating the device with a fibrosis-inducing composition,the fibrosing agent can be mixed with the materials that are used tomake the device such that the fibrosing agent is incorporated into thefinal device.

In addition to (or as an alternative to) applying the fibrosis agent tothe septal occlusion patch, an in situ forming composition, gel orthermogel composition containing a fibrosis-inducing agent can beapplied to (as a gel, solid implant, liquid or spray) the placement siteof the septal occlusion patch, either: (a) prior to placement of thepatch; (b) after placement of the patch; (c) during the placement of thepatch; or (d) any combination of those three. For the in situ formingthermogel and gel compositions, the fibrosis-inducing agent(s) (e.g.,silk powder, bleomycin) can be incorporated directly into theformulation to produce a suspension or a solution or it can beincorporated into a secondary carrier (e.g., micelles, liposomes,microspheres, microparticles, nanospheres, microparticulates, emulsionsand/or microemulsions) that is then incorporated into the in situforming compositions. In another embodiment, the fibrosis-inducing agentcan be electrostatically or covalently bound to one or more of thepolymeric components of the in-situ in situ forming composition.

In a particularly preferred embodiment, the composition may be preparedfrom a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and methylatedcollagen such as described above and contains a fibrosis-inducing agentthat is sprayed onto the surgical site to affix the septal occlusionpatch in place and induce fibrosis into the patch.

In another embodiment, the fibrosis-inducing agent can be incorporatedinto a biodegradable or dissolvable film or mesh that is then applied tothe treatment site prior to, or post, implantation of the septalocclusion patch. Exemplary materials for the manufacture of these filmsor meshes are hyaluronic acid (crosslinked or non-crosslinked),cellulose derivatives (e.g., hydroxypropyl cellulose), collagen andcrosslinked poly(ethylene glycol).

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use in septal occlusion patches include talc, silk,wool, chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well asanalogues and derivatives of the aforementioned.

As septal occlusion patches and compositions for use with septalocclusion patches are made in a variety of configurations and sizes, theexact dose administered can vary with patch size, surface area anddesign. However, certain principles can be applied in the application ofthis art. Drug dose can be calculated as a function of dose per unitarea (of the portion of the patch being coated), total drug doseadministered can be measured and appropriate surface concentrations ofactive drug can be determined. Regardless of the method of applicationof the drug to the septal occlusion patch, the exemplary fibrosingagents, used alone or in combination, should be administered under thefollowing dosing guidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the septal occlusion patch, or applied without a polymericcarrier, the total dose of talc delivered from a septal occlusion patch,or coated onto the surface of a septal occlusion patch, should notexceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the totalamount of talc released from the prosthesis should be in the range of 10μg to 50 mg. The dose per unit area of the implanted septal occlusionpatch (i.e., the dosage of talc as a function of the surface area of theportion of the septal occlusion patch to which drug is applied and/orincorporated) should fall within the range of 0.05 μg-10 μg per mm² ofsurface area coated. In another embodiment, talc should be applied to aseptal occlusion patch surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. In one embodiment, talc is released from thesurface of a septal occlusion patch such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, talc may be released in effective concentrations for a periodranging from 1 week to 9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of talc (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent astalc is administered at half the above parameters, a compound half aspotent as talc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the septal occlusion patch, or applied without a polymericcarrier, the total dose of silk delivered from a septal occlusion patch,or coated onto the surface of a septal occlusion patch, should notexceed 100 mg (range of 1 μg to 100 mg). In one embodiment, the totalamount of silk released from the septal occlusion patch should be in therange of 10 μg to 50 mg. The dose per unit area of the implanted septalocclusion patch (i.e., the dosage of silk as a function of the surfacearea of the portion of the septal occlusion patch to which drug isapplied and/or incorporated) should fall within the range of 0.05 μg-10μg per mm² of surface area coated. In another embodiment, silk should beapplied to a septal occlusion patch surface at a dose of 0.05 μg/mm²-10μg/mm² of surface area coated. As specific (polymeric and non-polymeric)drug delivery vehicles and specific septal occlusion patch can releasesilk at differing rates, the above dosing parameters should be utilizedin combination with the release rate of the drug from the septalocclusion patch such that a minimum concentration of 0.01 nM to 1000 μMof silk is delivered to the tissue. In one embodiment, silk is releasedfrom the surface of a septal occlusion patch such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, silk may be released in effective concentrationsfor a period ranging from 1 week-9 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofsilk (as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as silk is administered at half the above parameters, a compoundhalf as potent as silk is administered at twice the above parameters,etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the septal occlusion patch, or applied without a polymericcarrier, the total dose of chitosan delivered from a septal occlusionpatch, or coated onto the surface of a septal occlusion patch, shouldnot exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, thetotal amount of chitosan released from the septal occlusion patch shouldbe in the range of 10 μg to 50 mg. The dose per unit area of theimplanted septal occlusion patch (i.e., the dosage of chitosan as afunction of the surface area of the portion of the septal occlusionpatch to which drug is applied and/or incorporated) should fall withinthe range of 0.05 μg-10 μg per mm² of surface area coated. In anotherembodiment, chitosan should be applied to a septal occlusion patchsurface at a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. Asspecific (polymeric and non-polymeric) drug delivery vehicles andspecific septal occlusion patches can release chitosan at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the septal occlusion patch suchthat a minimum concentration of 0.01 nM to 1000 μM of chitosan isdelivered to the tissue. In one embodiment, chitosan is released fromthe surface of a septal occlusion patch such that fibrosis in the tissueis promoted for a period ranging from several hours to several months.For example, chitosan may be released in effective concentrations for aperiod ranging from 1 week to 9 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofchitosan (as described previously) with similar functional activity canbe utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as chitosan is administered at half the aboveparameters, a compound half as potent as chitosan is administered attwice the above parameters, etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the septal occlusion patch, or applied without a polymericcarrier, the total dose of polylysine delivered from a septal occlusionpatch, or coated onto the surface of a septal occlusion patch, shouldnot exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, thetotal amount of polylysine released from the septal occlusion patchshould be in the range of 10 μg to 50 mg. The dose per unit area of theimplanted septal occlusion patch (i.e., the dosage of polylysine as afunction of the surface area of the portion of the septal occlusionpatch to which drug is applied and/or incorporated) should fall withinthe range of 0.05 μg-10 μg per mm² of surface area coated. In anotherembodiment, polylysine should be applied to a septal occlusion patchsurface at a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. Asspecific (polymeric and non-polymeric) drug delivery vehicles andspecific septal occlusion patches can release polylysine at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the septal occlusion patch suchthat a minimum concentration of 0.01 nM to 1000 μM of polylysine isdelivered to the tissue. In one embodiment, polylysine is released fromthe surface of a septal occlusion patch such that fibrosis in the tissueis promoted for a period ranging from several hours to several months.For example, polylysine may be released in effective concentrations fora period ranging from 1 week to 9 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofpolylysine (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as polylysine is administered at half the aboveparameters, a compound half as potent as polylysine is administered attwice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the septal occlusion patch, or applied without a polymericcarrier, the total dose of fibronectin delivered from a septal occlusionpatch, or coated onto the surface of a septal occlusion patch, shouldnot exceed 100 mg (range of 1 μg to 100 mg). In one embodiment, thetotal amount of fibronectin released from the septal occlusion patchshould be in the range of 10 μg to 50 mg. The dose per unit area of theimplanted septal occlusion patch (i.e., the dosage of fibronectin as afunction of the surface area of the portion of the septal occlusionpatch to which drug is applied and/or incorporated) should fall withinthe range of 0.05 μg-10 μg per mm² of surface area coated. In anotherembodiment, fibronectin should be applied to a septal occlusion patchsurface at a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. Asspecific (polymeric and non-polymeric) drug delivery vehicles andspecific septal occlusion patches can release fibronectin at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the septal occlusion patch suchthat a minimum concentration of 0.01 nM to 1000 μM of fibronectin isdelivered to the tissue. In one embodiment, fibronectin is released fromthe surface of a septal occlusion patch such that fibrosis in the tissueis promoted for a period ranging from several hours to several months.For example, fibronectin may be released in effective concentrations fora period ranging from 1 week to 9 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives offibronectin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g., acompound twice as potent as fibronectin is administered at half theabove parameters, a compound half as potent as fibronectin isadministered at twice the above parameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the septal occlusion patch, or applied without a polymericcarrier, the total dose of bleomycin delivered from a septal occlusionpatch, or coated onto the surface of a septal occlusion patch, shouldnot exceed 100 mg (range of 0.01 μg to 100 mg). In one embodiment, thetotal amount of bleomycin released from the septal occlusion patchshould be in the range of 0.10 μg to 50 mg. The dose per unit area ofthe implanted septal occlusion patch (i.e., the dosage of bleomycin as afunction of the surface area of the portion of the patch to which drugis applied and/or incorporated) should fall within the range of 0.005μg-10 μg per mm² of surface area coated. In another embodiment,bleomycin should be applied to a septal occlusion patch surface at adose of 0.005 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specific septalocclusion patches can release bleomycin at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the septal occlusion patch such that a minimumconcentration of 0.001 nM to 1000 μM of bleomycin is delivered to thetissue. In one embodiment, bleomycin is released from the surface of aseptal occlusion patch such that fibrosis in the tissue is promoted fora period ranging from several hours to several months. For example,bleomycin may be released in effective concentrations for a periodranging from 1 week to 9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of bleomycin(as described previously) with similar functional activity can beutilized for the purposes of this invention; the above dosing parametersare then adjusted according to the relative potency of the analogue orderivative as compared to the parent compound (e.g., a compound twice aspotent as bleomycin is administered at half the above parameters, acompound half as potent as bleomycin is administered at twice the aboveparameters, etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the septal occlusion patch, or applied without a polymericcarrier, the total dose of CTGF delivered from a septal occlusion patch,or coated onto the surface of a septal occlusion patch, should notexceed 100 mg (range of 0.01 μg to 100 mg). In one embodiment, the totalamount of CTGF released from the septal occlusion patch should be in therange of 0.10 μg to 50 mg. The dose per unit area of the implantedseptal occlusion patch (i.e., the dosage of CTGF as a function of thesurface area of the portion of the septal occlusion patch to which drugis applied and/or incorporated) should fall within the range of 0.005μg-10 μg per mm² of surface area coated. In another embodiment, CTGFshould be applied to a septal occlusion patch surface at a dose of 0.005μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific septal occlusionpatches can release CTGF at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe septal occlusion patch such that a minimum concentration of 0.001 nMto 1000 μM of CTGF is delivered to the tissue. In one embodiment, CTGFis released from the surface of a septal occlusion patch such thatfibrosis in the tissue is promoted for a period ranging from severalhours to several months. For example, CTGF may be released in effectiveconcentrations for a period ranging from 1 week to 9 months. It shouldbe readily evident given the discussions provided herein that analoguesand derivatives of CTGF (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as CTGF is administered at half theabove parameters, a compound half as potent as CTGF is administered attwice the above parameters, etc.).

Optionally, the device or composition may alone or additionally comprisean inflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF,GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or ananalogue or derivative thereof. Inflammatory cytokines are to be used informulations at concentrations that range from 0.0001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the inflammatory cytokine is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.0001μg to 100 mg); preferred 0.001 μg to 50 mg. When used as a devicecoating, the dose is per unit area of 0.0001 μg-500 μg per mm²; with apreferred dose of 0.001 μg/mm²-200 μg/mm². Minimum concentration of10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to be maintained on thedevice surface.

Furthermore, the device or composition may alone or additionallycomprise an agent that stimulates cellular proliferation. Examplesinclude: dexamethasone, isotretinoin (13-cis retinoic acid),17-β-estradiol, estradiol, 1-a-25 dihydroxyvitamin D₃,diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid(ATRA), and analogues and derivatives thereof. Doses used are thoseconcentrations which are demonstrated to stimulate cell proliferation(see, e.g., Example 16). The proliferative agents are to be used informulations at concentrations that range from 0.0000001 to 25 mg/mldepending on the specific clinical application, formulation type (e.g.,gel, liquid, solid, semi-solid), formulation chemistry, duration ofrequired application, type of medical device interface and formulationvolume and or surface area coverage required. Preferably, theproliferative agent is released in effective concentrations for a periodranging from 1-180 days. The total dose for a single application istypically not to exceed 500 mg (range of 0.0001 μg to 200 mg); preferred0.001 μg to 100 mg. When used as a device coating, the dose is per unitarea of 0.00001 μg-500 μg per mm²; with a preferred dose of 0.0001μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

17. Endoluminal Fasteners

The present invention provides for the combination of afibrosis-inducing agent and an endoluminal fastener. Endoluminalfasteners may include, but are not limited to, staples (e.g.,endostaples), sutures, wires, filaments, cords, pins, clips and otherconnector devices and materials.

Endoluminal fasteners are devices that act like ribets to increase theintegrity of a damaged or perforated bodily tube or to secure anendoluminal graft to the wall of a bodily tube (e.g., blood vessel).Endoluminal fasteners may also be used in a variety of endoluminalsurgeries, such as, but not limited to, transmural polypectomies,resections of submucosal lesions, bowel resections, resections ofprocesses such as ulcers, controlling of bleeding, closing perforations,prophylactic or therapeutical appendectomies, resection of bleedingdiverticuli or Meckel's diverticulum, anchoring tubes or grafts (e.g.,anastomosis of a vascular artery to a graft), securing time-releasedmedications, performing gastroplasty, fallopian tubal ligation, solidorgan biopsies, bowel structuring or partial lung resectioning.

Endoluminal fasteners may be used by loading them into a deliverycatheter and then introducing them percutaneously into a bodily lumen.The catheter is then guided through the bodily tube to the site to berepaired. The fastener is delivered from the tip of the deliverycatheter so that it penetrates the desired site whereby the endoluminalfastener becomes secured to the wall of the bodily tube. The addition ofa fibrosis-inducing agent to the endoluminal fastener may encourage thedevelopment and ingrowth of strong, fibrous tissue in and around thedevice. Incorporation of a fibrosing agent into or onto an endoluminalfastener can promote tissue growth that can help anchor the device tothe wall of the lumen. Once the endoluminal fastener has been positionedacross the wall, part of it remains in the lumen, exposed to theconstituents of the bodily tube. For example, if the bodily tube was ablood vessel, the endoluminal fastener would be exposed to blood flowwhich can cause a thrombotic event. Thus, in another aspect of theinvention, the endoluminal fastener may further comprise ananti-thrombotic agent to prevent thrombus formation.

Endoluminal fasteners may be composed of biocompatible metals,including, but not limited to, nitinol, tantalum, stainless steel ormetallic alloys such as nickel, gold, silver, titanium nitride andchromium. Metallic fasteners have advantages when using them in aminimally invasive manner as the metal enables visualization duringendoscopic delivery via catheter. However, endoluminal fasteners mayalso be composed of biocompatible polymers and other synthetic ornatural materials either alone or in combination with metallicmaterials. These may include magnesium-based materials, plastics,ceramics, resin, protein-based materials, collagen and other similarmaterials. Non-metallic fasteners may be preferred in certainprocedures, for example, if there is a need for a bioabsorbable fasteneror to reduce the scattering of x-rays which occurs with metallicfasteners. Endoluminal fasteners may be made out of rigid, pliable,elastic, nonelastic, malleable, nonmalleable, retractable, ornonretractable material such that the fastener exerts the desired amountof pulling force required to attach to the luminal wall.

The endoluminal fasteners may be generally configured in a “T”, “H” or“U” shape. Metallic endoluminal fasteners are often secured in place bycrimping the fastener structure since they possess strength andductility. Endoluminal fasteners made of polymers and/or other materialsoften do not possess the same physical characteristics of the metallicfasteners. Therefore, fasteners made of polymers, for example, are oftenmade of two-parts, including a general U-shape fastener portion whichengages and interlocks its legs with a retainer portion.

In one aspect, the endoluminal fastener may be of a variety ofconfigurations and materials. For example, the endoluminal fastener maybe a single-tipped device having a curved configuration with a sharpenedend. See e.g., U.S. Pat. No. 6,491,707. The endoluminal fastener mayhave a stressed elongated shape and a second unstressed shape with aplurality of coils around a spring axis upon release from the deliveryelement. See e.g., U.S. Pat. No. 6,113,611. The endoluminal fastener maybe a suturing staple for passing through and securing tissue togetherwhereby the staple is positioned between lips of an endoluminalapparatus that aids in positioning, resecting and securing remainingtissue. See e.g., U.S. Pat. Nos. 6,264,086 and 5,868,760. Theendoluminal fastener may be adapted to incorporate a radiation sourcesuch that it provides radiation to a wound repair site. See e.g., U.S.Pat. No. 5,906,573. The endoluminal fastener may be composed of afastener and a retainer member made of resinous material which isabsorbable and exhibits improved hemostasis. See e.g., U.S. Pat. No.4,667,674. The endoluminal fastener may be composed of a shape-memorysurgical staple which may be formed as an open shape or closed shapebased on a transition temperature, whereby the heating of the staple byan electric current elevates the temperature of the staple which causesit to close and thus, join abutting tissue. See e.g., U.S. Pat. No.4,485,816. The endoluminal fastener may be a helical fastener having apenetrating end and a limiting end. See e.g., U.S. Pat. No. 6,592,593.The endoluminal fastener may be a pinned retainer surgical fastener thatmay be composed of a needle and a retainer that may be used to attach agraft to a vascular artery. See e.g., U.S. Pat. No. 6,074,401. Theendoluminal fastener may be of a general U-shape having parallel prongsand a retainer portion with apertures to retain the tips of respectiveprongs. See e.g., U.S. Pat. No. 5,292,334.

Commercially available endoluminal fasteners may also be combined withone or more fibrosis-inducing drugs according to the present invention.Examples of commercially available endoluminal fasteners are often soldwith an associated stapling device or endoscopic instrumentation. Forexample, Johnson & Johnson Gateway (Piscataway, N.J.) sells theirPROXIMATE ILS and ENDOPATH STEALTH Intraluminal Staplers which are usedfor anastomotic repair. Angiolink Corporation (Taunton, Mass.) sellstheir EVS Vascular Closure System. U.S. Surgical (Norwalk, Conn.) alsosells surgical stapling and endoscopic instrumentation.

In one aspect, the present invention provides an endoluminal fastenerthat includes a fibrosis-inducing agent to promote scarring between theendoluminal fastener and the blood vessel wall. The endoluminal fastenermay be coated with the fibrosing agent (with or without a carrier). Forexample, a fibrosis-inducing drug may be applied to the surface of theendoluminal fastener. Alternatively, or in addition, the endoluminalfastener may be composed either entirely or partially of a material thatis capable of inducing fibrosis. For example, silk strands or silk canbe affixed to the endoluminal fastener or the endoluminal fastener canbe composed partially or entirely of a fibrosing material (e.g., afibrosing polymer).

In another aspect, the present invention provides a sprayablecomposition that includes a fibrosis-inducing agent that can be used infastening procedures to promote scarring and attachment of anendoluminal fastener to a vessel wall.

Numerous polymeric and non-polymeric carrier systems described above maybe used in the practice of this embodiment. These compositions canfurther comprise one or more fibrosis-inducing agents to promote theformation of fibrous scar tissue. Methods for incorporating fibrosingcompositions onto or into endoluminal fasteners include: (a) directlyaffixing to the implant a fibrosing composition (e.g., by either aspraying process or dipping process as described above, with or withouta carrier); (b) directly incorporating into the device a fibrosingcomposition (e.g., by either a spraying process or dipping process asdescribed above, with or without a carrier); (c) by coating the devicewith a substance such as a hydrogel which can in turn absorb thefibrosing composition; (d) by interweaving fibrosing composition coatedthread (or the polymer itself formed into a thread) into the devicestructure; (e) by binding a film or mesh which is comprised of, orcoated with, a fibrosing composition to the endoluminal fastener; (f)constructing the device itself or a portion of the device with afibrosing composition; and/or (g) by covalently binding the fibrosingagent directly to the endoluminal fastener surface or to a linker (smallmolecule or polymer) that is coated or attached to the endoluminalfastener surface.

In addition to coating the device with a fibrosis-inducing composition,the fibrosing agent can be mixed with the materials that are used tomake the device such that the fibrosing agent is incorporated into thefinal device.

In addition to (or as an alternative to) applying the fibrosis agent tothe endoluminal fastener, an in situ forming composition, gel orthermogel composition containing a fibrosis-inducing agent can beapplied to (as a gel, solid implant, liquid or spray) the placement siteof the endoluminal fastener, either: (a) prior to placement of thefastener; (b) after placement of the fastener; (c) during the placementof the fastener; or (d) any combination of these. For the in situforming thermogel and gel compositions, the fibrosis-inducing agent(s)(e.g., silk powder, bleomycin) can be incorporated directly into theformulation to produce a suspension or a solution or it can beincorporated into a secondary carrier (e.g., micelles, liposomes,microspheres, microparticles, nanospheres, microparticulates, emulsionsand/or microemulsions) that is then incorporated into the in situforming compositions. In another embodiment, the fibrosis-inducing agentcan be electrostatically or covalently bound to one or more of thepolymeric components of the in-situ forming composition.

In a particularly preferred embodiment, the composition may be preparedfrom a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and methylatedcollagen such as described above and contains a fibrosis-inducing agentthat is sprayed onto the surgical site to affix the endoluminal fastenerin place and induce fibrosis between the fastener and the vessel wall.

In another embodiment, the fibrosis-inducing agent can be incorporatedinto a biodegradable or dissolvable film or mesh that is then applied tothe treatment site prior to, or post, implantation of the endoluminalfastener. Exemplary materials for the manufacture of these films ormeshes are hyaluronic acid (crosslinked or non-crosslinked), cellulosederivatives (e.g., hydroxypropyl cellulose), collagen and crosslinkedpoly(ethylene glycol).

It should be apparent to one of skill in the art that potentially anyadhesion or fibrosis-inducing agents described above may be utilizedalone, or in combination, in the practice of this embodiment. Exemplaryfibrosing agents for use with endoluminal fasteners include talc, silk,wool, chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well asanalogues and derivatives of the aforementioned.

As endoluminal fasteners and compositions for use with endoluminalfasteners are made in a variety of configurations and sizes, the exactdose administered can vary with staple size, surface area and design.However, certain principles can be applied in the application of thisart. Drug dose can be calculated as a function of dose per unit area (ofthe portion of the patch being coated), total drug dose administered canbe measured and appropriate surface concentrations of active drug can bedetermined. Regardless of the method of application of the drug to theendoluminal fastener, the exemplary fibrosing agents, used alone or incombination, should be administered under the following dosingguidelines:

Utilizing talc as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the endostaples, or applied without a polymeric carrier, thetotal dose of talc delivered from an endostaple, or coated onto thesurface of an endostaple, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of talc released from theprosthesis should be in the range of 10 μg to 50 mg. The dose per unitarea of the implanted endostaple (i.e., the dosage of talc as a functionof the surface area of the portion of the endostaple to which drug isapplied and/or incorporated) should fall within the range of 0.05 μg-10μg per mm² of surface area coated. In another embodiment, talc should beapplied to an endostaple surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. In one embodiment, talc is released from thesurface of an endostaple such that fibrosis in the tissue is promotedfor a period ranging from several hours to several months. For example,talc may be released in effective concentrations for a period rangingfrom 1 week to 9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of talc (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent astalc is administered at half the above parameters, a compound half aspotent as talc is administered at twice the above parameters, etc.).

Utilizing silk as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the endostaple, or applied without a polymeric carrier, thetotal dose of silk delivered from an endostaple, or coated onto thesurface of an endostaple, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of silk released from theendostaple should be in the range of 10 μg to 50 mg. The dose per unitarea of the implanted endostaple (i.e., the dosage of silk as a functionof the surface area of the portion of the endostaple to which drug isapplied and/or incorporated) should fall within the range of 0.05 μg-10μg per mm² of surface area coated. In another embodiment, silk should beapplied to an endostaple surface at a dose of 0.05 μg/mm²-10 μg/mm² ofsurface area coated. As specific (polymeric and non-polymeric) drugdelivery vehicles and specific endostaple can release silk at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the endostaple such that aminimum concentration of 0.01 nM to 1000 μM of silk is delivered to thetissue. In one embodiment, silk is released from the surface of anendostaple such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, silk may bereleased in effective concentrations for a period ranging from 1 week-9months. It should be readily evident given the discussions providedherein that analogues and derivatives of silk (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g., a compound twice as potent as silk isadministered at half the above parameters, a compound half as potent assilk is administered at twice the above parameters, etc.).

Utilizing chitosan as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the endostaple, or applied without a polymeric carrier, thetotal dose of chitosan delivered from an endostaple, or coated onto thesurface of an endostaple, should not exceed 100 mg (range of 1 μg to 100mg). In one embodiment, the total amount of chitosan released from theendostaple should be in the range of 10 μg to 50 mg. The dose per unitarea of the implanted endostaple (i.e., the dosage of chitosan as afunction of the surface area of the portion of the endostaple to whichdrug is applied and/or incorporated) should fall within the range of0.05 μg-10 μg per mm² of surface area coated. In another embodiment,chitosan should be applied to an endostaple surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific endostaples canrelease chitosan at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from theendostaple such that a minimum concentration of 0.01 nM to 1000 μM ofchitosan is delivered to the tissue. In one embodiment, chitosan isreleased from the surface of an endostaple such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, chitosan may be released in effectiveconcentrations for a period ranging from 1 week to 9 months. It shouldbe readily evident given the discussions provided herein that analoguesand derivatives of chitosan (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as chitosan is administered at halfthe above parameters, a compound half as potent as chitosan isadministered at twice the above parameters, etc.).

Utilizing polylysine as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the endostaple, or applied without a polymeric carrier, thetotal dose of polylysine delivered from an endostaple, or coated ontothe surface of an endostaple, should not exceed 100 mg (range of 1 μg to100 mg). In one embodiment, the total amount of polylysine released fromthe endostaple should be in the range of 10 μg to 50 mg. The dose perunit area of the implanted endostaple (i.e., the dosage of polylysine asa function of the surface area of the portion of the endostaple to whichdrug is applied and/or incorporated) should fall within the range of0.05 μg-10 μg per mm² of surface area coated. In another embodiment,polylysine should be applied to an endostaple surface at a dose of 0.05μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific endostaples canrelease polylysine at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe endostaple such that a minimum concentration of 0.01 nM to 1000 μMof polylysine is delivered to the tissue. In one embodiment, polylysineis released from the surface of an endostaple such that fibrosis in thetissue is promoted for a period ranging from several hours to severalmonths. For example, polylysine may be released in effectiveconcentrations for a period ranging from 1 week to 9 months. It shouldbe readily evident given the discussions provided herein that analoguesand derivatives of polylysine (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g., a compound twice as potent as polylysine is administered at halfthe above parameters, a compound half as potent as polylysine isadministered at twice the above parameters, etc.).

Utilizing fibronectin as an exemplary fibrosis-inducing agent, whetherit is applied using a polymer coating, incorporated into the polymerswhich make up the endostaple, or applied without a polymeric carrier,the total dose of fibronectin delivered from an endostaple, or coatedonto the surface of an endostaple, should not exceed 100 mg (range of 1μg to 100 mg). In one embodiment, the total amount of fibronectinreleased from the endostaple should be in the range of 10 μg to 50 mg.The dose per unit area of the implanted endostaple (i.e., the dosage offibronectin as a function of the surface area of the portion of theendostaple to which drug is applied and/or incorporated) should fallwithin the range of 0.05 μg-10 μg per mm² of surface area coated. Inanother embodiment, fibronectin should be applied to an endostaplesurface at a dose of 0.05 μg/mm²-10 μg/mm² of surface area coated. Asspecific (polymeric and non-polymeric) drug delivery vehicles andspecific endostaples can release fibronectin at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the endostaple such that a minimumconcentration of 0.01 nM to 1000 μM of fibronectin is delivered to thetissue. In one embodiment, fibronectin is released from the surface ofan endostaple such that fibrosis in the tissue is promoted for a periodranging from several hours to several months. For example, fibronectinmay be released in effective concentrations for a period ranging from 1week to 9 months. It should be readily evident given the discussionsprovided herein that analogues and derivatives of fibronectin (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asfibronectin is administered at half the above parameters, a compoundhalf as potent as fibronectin is administered at twice the aboveparameters, etc.).

Utilizing bleomycin as an exemplary fibrosis-inducing agent, whether itis applied using a polymer coating, incorporated into the polymers whichmake up the endostaple, or applied without a polymeric carrier, thetotal dose of bleomycin delivered from an endostaple, or coated onto thesurface of an endostaple, should not exceed 100 25 mg (range of 0.01 μgto 100 25 mg). In one embodiment, the total amount of bleomycin releasedfrom the endostaple should be in the range of 0.10 μg to 50 25 mg. Thedose per unit area of the implanted endostaple (i.e., the dosage ofbleomycin as a function of the surface area of the portion of the patchto which drug is applied and/or incorporated) should fall within therange of 0.005 μg-10 μg per mm² of surface area coated. In anotherembodiment, bleomycin should be applied to an endostaple surface at adose of 0.005 μg/mm²-10 μg/mm² of surface area coated. As specific(polymeric and non-polymeric) drug delivery vehicles and specificendostaples can release bleomycin at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the endostaple such that a minimum concentration of 0.001nM to 1000 μM of bleomycin is delivered to the tissue. In oneembodiment, bleomycin is released from the surface of an endostaple suchthat fibrosis in the tissue is promoted for a period ranging fromseveral hours to several months. For example, bleomycin may be releasedin effective concentrations for a period ranging from 1 week to 9months. It should be readily evident given the discussions providedherein that analogues and derivatives of bleomycin (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asbleomycin is administered at half the above parameters, a compound halfas potent as bleomycin is administered at twice the above parameters,etc.).

Utilizing CTGF as an exemplary fibrosis-inducing agent, whether it isapplied using a polymer coating, incorporated into the polymers whichmake up the endostaple, or applied without a polymeric carrier, thetotal dose of CTGF delivered from an endostaple, or coated onto thesurface of an endostaple, should not exceed 100 25 mg (range of 0.01 μgto 100 mg). In one embodiment, the total amount of CTGF released fromthe endostaple should be in the range of 0.10 μg to 50 25 mg. The doseper unit area of the implanted endostaple (i.e., the dosage of CTGF as afunction of the surface area of the portion of the endostaple to whichdrug is applied and/or incorporated) should fall within the range of0.005 μg-10 μg per mm² of surface area coated. In another embodiment,CTGF should be applied to an endostaple surface at a dose of 0.005μg/mm²-10 μg/mm² of surface area coated. As specific (polymeric andnon-polymeric) drug delivery vehicles and specific endostaples canrelease CTGF at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from theendostaple such that a minimum concentration of 0.001 nM to 1000 μM ofCTGF is delivered to the tissue. In one embodiment, CTGF is releasedfrom the surface of an endostaple such that fibrosis in the tissue ispromoted for a period ranging from several hours to several months. Forexample, CTGF may be released in effective concentrations for a periodranging from 1 week to 9 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of CTGF (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asCTGF is administered at half the above parameters, a compound half aspotent as CTGF is administered at twice the above parameters, etc.).

Optionally, the device or composition may alone or additionally comprisean inflammatory cytokine (e.g., TGFβ, PDGF, VEGF, bFGF, TNFα, NGF,GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or ananalogue or derivative thereof. Inflammatory cytokines are to be used informulations at concentrations that range from 0.0001 μg/ml toapproximately 20 mg/ml depending on the specific clinical application,formulation type (e.g., gel, liquid, solid, semi-solid), formulationchemistry, duration of required application, type of medical deviceinterface and formulation volume and or surface area coverage required.Preferably, the inflammatory cytokine is released in effectiveconcentrations for a period ranging from 1-180 days. The total dose fora single application is typically not to exceed 500 mg (range of 0.0001μg to 100 mg); preferred 0.001 μg to 50 mg. When used as a devicecoating, the dose is per unit area of 0.0001 μg-500 μg per mm²; with apreferred dose of 0.001 μg/mm²-200 μg/mm². Minimum concentration of10⁻¹⁰-10⁻⁴ g/ml of inflammatory cytokine is to be maintained on thedevice surface.

Furthermore, the device or composition may alone or additionallycomprise an agent that stimulates cellular proliferation. Examplesinclude: dexamethasone, isotretinoin (13-cis retinoic acid),17-β-estradiol, estradiol, 1-a-25 dihydroxyvitamin D₃,diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid(ATRA), and analogues and derivatives thereof. Doses used are thoseconcentrations which are demonstrated to stimulate cell proliferation(see, e.g., Example 16). The proliferative agents are to be used informulations at concentrations that range from 0.0000001 to 25 mg/mldepending on the specific clinical application, formulation type (e.g.,gel, liquid, solid, semi-solid), formulation chemistry, duration ofrequired application, type of medical device interface and formulationvolume and or surface area coverage required. Preferably, theproliferative agent is released in effective concentrations for a periodranging from 1-180 days. The total dose for a single application istypically not to exceed 500 mg (range of 0.0001 μg to 200 mg); preferred0.001 μg to 100 mg. When used as a device coating, the dose is per unitarea of 0.00001 μg-500 μg per mm²; with a preferred dose of 0.0001μg/mm²-200 μg/mm². Minimum concentration of 10⁻¹¹-10⁻⁶ M ofproliferative agent is to be maintained on the device surface.

It should be readily evident to one of skill in the art that any of thepreviously described fibrosis inducing agents, or derivatives andanalogues thereof, can be utilized to create variations of the abovecompositions without deviating from the spirit and scope of theinvention. It should also be apparent that the agent can be utilized ina composition with or without polymer carrier and that altering thecarrier does not deviate from the scope of this invention.

For all the previously described embodiments, suitable fibrosis-inducingagents include tissue irritants such tissue as silk, silica, bleomycin,neomycin, talcum powder, metallic beryllium, and copper are particularlysuitable for the practice of this invention. Other agents which may beincorporated into or onto the implant or device or released from theimplant or device include extracellular matrix components such asfibrous structural proteins (e.g., fibrillar collagens, nonfibrillarcollagen and elastins), adhesive glycoproteins (e.g., laminin andfibronectin), proteoglycans (e.g., heparin sulfate, chondroitin sulfate,dermatan sulfate), hyaluronan (e.g., hyaluronic acid), secreted proteinacidic and rich in cysteine (SPARC), thrombospondins, tenacin,inhibitors of matrix metalloproteinases (e.g., TIMPs and synthetic TIMPssuch as marimistat, batimistat, doxycycline, tetracycline, minocycline,TROCADE, Ro-1130830, CGS 27023A, BMS-275291) and polylysine. Growthfactors and inflammatory cytokines involved in angiogenesis, fibroblastmigration, fibroblast proliferation, ECM synthesis and tissue remodelingsuch as epidermal growth factor (EGF) family, transforming growthfactor-α (TGF-α), transforming growth factor-β (TGF-9-1, TGF-9-2,TGF-9-3), platelet-derived growth factor (PDGF), fibroblast growthfactor (acidic—aFGF; and basic—bFGF), bone morphogenic proteins,activins, vascular endothelial growth factor (VEGF, VEGF-B, VEGF-C,placental growth factor—PIGF), angiopoietins, insulin-like growthfactors (IGF), hepatocyte growth factor (HGF), connective tissue growthfactor (CTGF), myeloid colony-stimulating factors (CSFs),granulocyte-macrophage colony-stimulating factors (GM-CSF), granulocytecolony-stimulating factor (G-CSF), macrophage colony-stimulating factor(M-CSF), erythropoietin, interleukins (particularly IL-1, IL-8, IL-6),tumor necrosis factor-α (TNF9), nerve growth factor (NGF), interferon-α,interferon-β, and growth hormone (GH) are also suitable for release fromspecific implants and devices. Other agents which may be coated onto orreleased by the implant or device include adhesives such ascyanoacrylate or materials made from 4-armed thiol PEG (10K), a 4-armedNHS PEG(10K) and methylated collagen such as described above.

Within related aspects of the present invention, orthopaedic implants(artificial joints, artificial ligaments and tendons, screws, plates,and the like), dental implants, intravascular implants (particularlyarterial and venous occlusion, vascular destructive implants), male andfemale contraceptive or sterilization devices and implants, implantabletissue bulking agents for incontinence (esophageal, urethral, anal),soft palate implants, embolization agents, pulmonary sealants, surgicalmeshes (e.g., hernia repair meshes, tissue scaffolds), and spinalimplants (e.g., artificial discs) are provided comprising an implant ordevice, wherein the implant or device releases an agent which inducesfibrosis in vivo.

In one aspect, methods are provided for manufacturing a medical deviceor implant that release a fibrosis agent. Within yet other aspects ofthe present invention, methods are provided for manufacturing a medicaldevice or implant, comprising the step of coating (e.g., spraying,dipping, wrapping, or administering drug through) a medical device orimplant. Additionally, the implant or medical device can be constructedso that the device itself is comprised of materials, which inducefibrosis in or around the implant. A wide variety of medical devices andimplants may be utilized within the context of the present invention,depending on the site and nature of treatment desired.

Within various embodiments of the invention, the implant or device isfurther coated with a composition or compound, which delays the onset ofactivity of the fibrosis-inducing agent for a period of time afterimplantation. Representative examples of such agents include heparin,PLGA/MePEG, PLA, and polyethylene glycol. Within further embodiments thefibrosis-inducing implant or device is activated before, during, orafter deployment (e.g., an inactive agent on the device is firstactivated to one that induces or accelerates an in vivo fibroticreaction).

Within various embodiments of the invention, a device or implant iscoated one one aspect, portion or surface with a composition whichpromotes fibrosis, as well as being coated with a composition orcompound which prevents scarring on another aspect, potion or surface ofthe device. Representative examples of agents that inhibit fibrosis andscarring include paclitaxel, sirolimus, everolimus, as well as analoguesand derivatives thereof. Other examples are described in co-pendingapplication entitled, “Medical Implants and Anti-Scarring Agents” (U.S.Ser. No. 60/523,908), filed Nov. 20, 2003 and (U.S. Ser. No.60/586,861), filed Jul. 9, 2004.

Also provided by the present invention are methods for treating patientsundergoing surgical, endoscopic or minimally invasive therapies where amedical device or implant is placed as part of the procedure. Asutilized herein, it should be understood that “induces fibrosis” refersto a statistically significant increase in the amount of scar tissuearound the device or an improvement in the incorporation of thedevice/implant into the surrounding tissue and not to a permanentprohibition of any complications or failures of the device/implant.

The present invention also provides the following itemized embodiments.

1. A method comprising introducing into an intervertebral disc space ofa patient in need thereof, a therapeutically effective amount of afibrosing agent or a composition comprising a fibrosing agent, where thefibrosing agent induces a fibrotic response at the intervertebral discspace of the patient, thereby providing the patient with a beneficialresult.

2. The method of item 1 wherein beneficial result is the repair of aspinal disc.

3. The method of item 1 wherein the beneficial result is fibrousankylosis.

4. The method of item 1 wherein the beneficial result is bony ankylosis.

5. The method of item 1 wherein the fibrosing agent promotesregeneration.

6. The method of item 1 wherein the fibrosing agent promotesangiogenesis.

7. The method of item 1 wherein the fibrosing agent promotes fibroblastmigration.

8. The method of item 1 wherein the fibrosing agent promotes fibroblastproliferation.

9. The method of item 1 wherein the fibrosing agent promotes depositionof extracellular matrix (ECM).

10. The method of item 1 wherein the fibrosing agent promotes tissueremodeling.

11. The method of item 1 wherein the fibrosing agent is an arterialvessel wall irritant.

12. The method of item 1 wherein the fibrosing agent is or comprisessilk.

13. The method of item 1 wherein the fibrosing agent is or comprisessilkworm silk.

14. The method of item 1 wherein the fibrosing agent is or comprisesspider silk.

15. The method of item 1 wherein the fibrosing agent is or comprisesrecombinant silk.

16. The method of item 1 wherein the fibrosing agent is or comprises rawsilk.

17. The method of item 1 wherein the fibrosing agent is or compriseshydrolyzed silk.

18. The method of item 1 wherein the fibrosing agent is or comprisesacid-treated silk.

19. The method of item 1 wherein the fibrosing agent is or comprisesacylated silk.

20. The method of item 1 wherein the fibrosing agent is in the form ofstrands.

21. The method of item 1 wherein the fibrosing agent is in the form oftufts.

22. The method of item 1 wherein the fibrosing agent is in the form ofmicroparticulates.

23. The method of item 1 wherein the fibrosing agent is or comprisesmineral particles.

24. The method of item 1 wherein the fibrosing agent is or comprisestalc.

25. The method of item 1 wherein the fibrosing agent is or compriseschitosan.

26. The method of item 1 wherein the fibrosing agent is or comprisespolylysine.

27. The method of item 1 wherein the fibrosing agent is or comprisesfibronectin.

28. The method of item 1 wherein the fibrosing agent is or comprisesbleomycin.

29. The method of item 1 wherein the fibrosing agent is or comprisesCTGF.

30. The method of item 1 wherein the fibrosing agent is in the form of athread, or is in contact with a thread.

31. The method of item 30 wherein the thread is biodegradable.

32. The method of item 31 wherein the biodegradable thread comprises amaterial selected from the group consisting of polyester, polyanhydride,poly(anhydride ester), poly(ester-amide), poly(ester-urea),polyorthoester, polyphosphoester, polyphosphazine, polycyanoacrylate,collagen, chitosan, hyaluronic acid, chromic cat gut, alginate, starch,cellulose and cellulose ester.

33. The method of item 30 wherein the thread is non-biodegradable.

34. The method of item 33 wherein the non-biodegradable thread comprisesa material selected from the group consisting of polyester,polyurethane, silicone, polyethylene, polypropylene, polystyrene,polyacrylate, polymethacrylate, and silk.

35. The method of item 30 wherein the thread is coated with a polymer.

36. The method of item 30 wherein the thread is coated with apharmaceutical agent that induces a fibrotic response in the patient.

37. The method of item 30 wherein the thread is coated with apharmaceutical agent that induces an osteogenic response in the patient.

38. The method of item 30 wherein the fibrosing agent is in the form ofa particulate.

39. The method of item 38 wherein the particulate is a biodegradableparticulate.

40. The method of item 39 wherein the biodegradable particulatecomprises a material selected from the group consisting of polyester,polyanhydride, poly(anhydride ester), poly(ester-amide),poly(ester-urea), polyorthoester, polyphosphoester, polyphosphazine,polycyanoacrylate, collagen, chitosan, hyaluronic acid, chromic cat gut,alginate, starch, cellulose and cellulose ester.

41. The method of item 38 wherein the particulate is non-biodegradable.

42. The method of item 41 wherein the non-biodegradable particulatecomprises a material selected from the group consisting of polyester,polyurethane, silicone, polyethylene, polypropylene, polystyrene,polyacrylate, polymethacrylate, and silk.

43. The method of item 38 wherein the particulate is a particulate formof a member selected from the group consisting of silk, talc, starch,glass, silicate, silica, calcium phosphate, calcium sulfate, calciumcarbonate, hydroxyapatite, synthetic mineral, polymethylmethacrylate,silver nitrate, ceramic and other inorganic particles.

44. The method of item 38 wherein the particulate is coated with apolymer.

45. The method of item 38 wherein the particulate is coated with apharmaceutical agent that induces a fibrotic response in the patient.

46. The method of item 38 wherein the particulate is coated with amember selected from the group consisting of silk, talc, starch, glass,silicate, silica, calcium phosphate, calcium sulfate, calcium carbonate,hydroxyapatite, synthetic mineral, polymethylmethacrylate, silvernitrate, ceramic and other inorganic particles.

47. The method of item 38 wherein the particulate is coated with apharmaceutical agent that induces an osteogenic response in the patient.

48. The method of item 1 wherein the composition further comprises anagent that promotes bone growth.

49. The method of item 48 wherein the fibrosing agent that promotes bonegrowth is a bone morphogenic protein.

50. The method of item 48 wherein the fibrosing agent that promotes bonegrowth is an osteogenic growth factor.

51. The method of item 50 wherein the osteogenic growth factor isselected from transforming growth factor, platelet-derived growthfactor, and fibroblast growth factor.

52. The method of item 1 wherein the composition further comprises apharmaceutical agent that induces sclerosis (a sclerosant).

53. The method of item 52 wherein the sclerosant is selected from thegroup consisting of ethanol, dimethyl sulfoxide, sucrose, sodiumchloride, dextrose, glycerin, minocycline, tetracycline, doxycycline,polidocanol, sodium tetradecyl sulfate, sodium morrhuate, andsotradecol.

54. The method of item 52 wherein the sclerosant is a surfactant.

55. The method of item 1 wherein the composition further comprises aninflammatory cytokine.

56. The method of item 55 wherein the inflammatory cytokine is selectedfrom the group consisting of TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF,IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone.

57. The method of item 1 wherein the composition further comprises anagent that stimulates cell proliferation.

58. The method of item 57 wherein the fibrosing agent that stimulatescell proliferation is selected from the group consisting ofdexamethasone, isotretinoin (13-cis retinoic acid), 17-β-estradiol,estradiol, 1-a-25 dihydroxyvitamin D₃, diethylstibesterol, cyclosporineA, L-NAME, all-trans retinoic acid (ATRA), and analogues and derivativesthereof.

59. The method of item 1 wherein the composition further comprises abulking agent.

60. The method of item 1 wherein the composition further comprises asealant.

61. The method of item 1 wherein the composition further comprises apolymeric carrier.

62. The method of item 61 wherein the polymeric carrier providessustained release for an active component of the composition.

63. The method of item 61 wherein the polymeric carrier is anon-biodegradable material.

64. The method of item 63 wherein the non-biodegradable material iscrosslinked.

65. The method of item 64 wherein the crosslinked non-biodegradablematerial comprises a crosslinked form of polyvinylalcohol,polyvinylpyrrolidone, polyacrylamide, methyl methacrylate or methylmethacrylate-styrene copolymer.

66. The method of item 63 wherein the non-biodegradable material is ahydogel.

67. The method of item 61 wherein the polymeric carrier is abiodegradable material.

68. The method of item 67 wherein the biodegradable material is acrosslinked material prepared from, or incorporating units of,polyethyleneglycol, gelatin, collagen, bone allografts, mesenchymal stemcells, hyaluronic acid, hyaluronic acid derivatives, polysaccharides,carbohydrates, proteins, autologous bone, demineralized bone matrix,cellulose derivatives, chitosan, chitosan derivatives, andpolyester-polyalkylene oxide block copolymers.

69. The method of item 61 wherein the polymeric carrier is prepared froma 4-armed thiol PEG, a 4-armed NHS PEG, and methylated collagen.

70. The method of item 1 wherein the composition further comprises aresorbable ceramic.

71. The method of item 70 wherein the resorbable ceramic comprises, oris prepared from, a material selected from the group consisting of□-tricalcium phosphate, hydroxyapatite, Ca₁₀(PO₄)₆OH, calcium carbonate,calcium sulfate and calcium phosphate.

72. The method of item 1 wherein the composition further comprises acontrast agent.

73. The method of item 72 wherein the contrast agent responds to x-ray.

74. The method of item 73 wherein the contrast agent is barium,tantalum, technetium, or gadolinium.

75. The method of item 1 wherein the composition further comprises athread.

76. The method of item 75 wherein the thread is biodegradable.

77. The method of item 76 wherein the biodegradable thread comprises amaterial selected from the group consisting of polyester, polyanhydride,poly(anhydride ester), poly(ester-amide), poly(ester-urea),polyorthoester, polyphosphoester, polyphosphazine, polycyanoacrylate,collagen, chitosan, hyaluronic acid, chromic cat gut, alginate, starch,cellulose and cellulose ester.

78. The method of item 75 wherein the thread is non-biodegradable.

79. The method of item 78 wherein the non-biodegradable thread comprisesa material selected from the group consisting of polyester,polyurethane, silicone, polyethylene, polypropylene, polystyrene,polyacrylate, polymethacrylate, and silk.

80. The method of item 75 wherein the thread is coated with a polymer.

81. The method of item 75 wherein the thread is coated with apharmaceutical agent that induces a fibrotic response in the patient.

82. The method of item 75 were in wherein the thread is coated with apharmaceutical agent that induces a osteogenic response in the patient.

83. The method of item 1 wherein the composition is in the form of agel.

84. The method of item 1 wherein the composition is in the form of apaste.

85. The method of item 1 wherein the composition is in the form of aspray.

86. The method of item 1 wherein the composition is in the form of anaerosol.

87. The method of item 1 wherein the composition is in the form of asuspension.

88. The method of item 1 wherein the composition is in the form of anemulsion or microemulsion.

89. The method of item 1 wherein the composition is in the form of amicrosphere.

90. The method of item 1 wherein the composition is in the form of amicroparticulate.

91. The method of item 1 wherein the composition is in the form of asolid implant.

92. An injectable composition comprising a fibrosing agent and a bulkingagent.

93. The composition of item 92 wherein the fibrosing agent promotesfibrosis and promotes regeneration.

94. The composition of item 92 wherein the fibrosing agent promotesangiogenesis.

95. The composition of item 92 wherein the fibrosing agent promotesfibroblast migration.

96. The composition of item 92 wherein the fibrosing agent promotesfibroblast proliferation.

97. The composition of item 92 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

98. The composition of item 92 wherein the fibrosing agent promotestissue remodeling.

99. The composition of item 92 wherein the fibrosing agent is anarterial vessel wall irritant.

100. The composition of item 92 wherein the fibrosing agent is orcomprises silk.

101. The composition of item 92 wherein the fibrosing agent is orcomprises silkworm silk.

102. The composition of item 92 wherein the fibrosing agent is orcomprises spider silk.

103. The composition of item 92 wherein the fibrosing agent is orcomprises recombinant silk.

104. The composition of item 92 wherein the fibrosing agent is orcomprises raw silk.

105. The composition of item 92 wherein the fibrosing agent is orcomprises hydrolyzed silk.

106. The composition of item 92 wherein the fibrosing agent is orcomprises acid-treated silk.

107. The composition of item 92 wherein the fibrosing agent is orcomprises acylated silk.

108. The composition of item 92 wherein the fibrosing agent is in theform of strands.

109. The composition of item 92 wherein the fibrosing agent is in theform of tufts.

110. The composition of item 92 wherein the fibrosing agent is in theform of microparticulates.

111. The composition of item 92 wherein the fibrosing agent is orcomprises mineral particles.

112. The composition of item 92 wherein the fibrosing agent is orcomprises talc.

113. The composition of item 92 wherein the fibrosing agent is orcomprises chitosan.

114. The composition of item 92 wherein the fibrosing agent is orcomprises polylysine.

115. The composition of item 92 wherein the fibrosing agent is orcomprises fibronectin.

116. The composition of item 92 wherein the fibrosing agent is orcomprises bleomycin.

117. The composition of item 92 wherein the fibrosing agent is orcomprises CTGF.

118. The composition of item 92 wherein the fibrosing agent is in theform of a thread, or is in contact with a thread.

119. The composition of item 118 wherein the thread is biodegradable.

120. The composition of item 119 wherein the biodegradable threadcomprises a material selected from the group consisting of polyester,polyanhydride, poly(anhydride ester), poly(ester-amide),poly(ester-urea), polyorthoester, polyphosphoester, polyphosphazine,polycyanoacrylate, collagen, chitosan, hyaluronic acid, chromic cat gut,alginate, starch, cellulose and cellulose ester.

121. The composition of item 118 wherein the thread isnon-biodegradable.

122. The composition of item 121 wherein the non-bioderadable threadcomprises a material selected from the group consisting of polyester,polyurethane, silicone, polyethylene, polypropylene, polystyrene,polyacrylate, polymethacrylate, and silk.

123. The composition of item 118 wherein the thread is coated with apolymer.

124. The composition of item 118 wherein the thread is coated with apharmaceutical agent that induces a fibrotic response in the patient.

125. The composition of item 118 wherein the thread is coated with apharmaceutical agent that induces an osteogenic response in the patient.

126. The composition of item 92 wherein the fibrosing agent is in theform of a particulate.

127. The composition of item 126 wherein the particulate is abiodegradable particulate.

128. The composition of item 127 wherein the biodegradable particulatecomprises a material selected from the group consisting of polyester,polyanhydride, poly(anhydride ester), poly(ester-amide),poly(ester-urea), polyorthoester, polyphosphoester, polyphosphazine,polycyanoacrylate, collagen, chitosan, hyaluronic acid, chromic cat gut,alginate, starch, cellulose and cellulose ester.

129. The composition of item 126 wherein the particulate isnon-biodegradable.

130. The composition of item 129 wherein the non-biodegradableparticulate comprises a material selected from the group consisting ofpolyester, polyurethane, silicone, polyethylene, polypropylene,polystyrene, polyacrylate, polymethacrylate, and silk.

131. The composition of item 126 wherein the particulate is aparticulate form of a member selected from the group consisting of silk,talc, starch, glass, silicate, silica, calcium phosphate, calciumsulfate, calcium carbonate, hydroxyapatite, synthetic mineral,polymethylmethacrylate, silver nitrate, ceramic and other inorganicparticles.

132. The composition of item 126 wherein the particulate is coated witha polymer.

133. The composition of item 126 wherein the particulate is coated witha pharmaceutical agent that induces a fibrotic response in the patient.

134. The composition of item 126 wherein the particulate is coated witha member selected from the group consisting of silk, talc, starch,glass, silicate, silica, calcium phosphate, calcium sulfate, calciumcarbonate, hydroxyapatite, synthetic mineral, polymethylmethacrylate,silver nitrate, ceramic and other inorganic particles.

135. The composition of item 126 wherein the particulate is coated witha pharmaceutical agent that induces an osteogenic response in thepatient.

136. The composition of item 92 wherein the composition furthercomprises an agent that promotes bone growth.

137. The composition of item 136 wherein the fibrosing agent thatpromotes bone growth is a bone morphogenic protein.

138. The composition of item 136 wherein the fibrosing agent thatpromotes bone growth is an osteogenic growth factor.

139. The composition of item 138 wherein the osteogenic growth factor isselected from transforming growth factor, platelet-derived growthfactor, and fibroblast growth factor.

140. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with treatment of a shoulder capsule injury.

141. The method of item 140 wherein the agent promotes regeneration.

142. The method of item 140 wherein the agent promotes angiogenesis.

143. The method of item 140 wherein the agent promotes fibroblastmigration.

144. The method of item 140 wherein the agent promotes fibroblastproliferation.

145. The method of item 140 wherein the agent promotes deposition ofextracellular matrix (ECM).

146. The method of item 140 wherein the agent promotes tissueremodeling.

147. The method of item 140 wherein the agent is an arterial vessel wallirritant.

148. The method of item 140 wherein the fibrosing agent is or comprisessilk.

149. The method of item 140 wherein the fibrosing agent is in the formof tufts.

150. The method of item 140 wherein the fibrosing agent is or comprisesmineral particles.

151. The method of item 140 wherein the fibrosing agent is or compriseschitosan.

152. The method of item 140 wherein the fibrosing agent is or comprisespolylysine.

153. The method of item 140 wherein the fibrosing agent is or comprisesfibronectin.

154. The method of item 140 wherein the fibrosing agent is or comprisesbleomycin.

155. The method of item 140 wherein the fibrosing agent is or comprisesCTGF.

156. The method of item 140 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

157. The method of item 140 wherein the fibrosing agent is in the formof a particulate.

158. The method of item 140, wherein the composition comprises apolymer.

159. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

160. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

161. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

162. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

163. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

164. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

165. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

166. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

167. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

168. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

169. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

170. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

171. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

172. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

173. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

174. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

175. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

176. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

177. The method of item 140, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

178. The method of item 140, wherein the composition further comprises asecond pharmaceutically active agent.

179. The method of item 140, wherein the composition further comprisesan anti-inflammatory agent.

180. The method of item 140, wherein the composition further comprisesan agent that inhibits infection.

181. The method of item 140, wherein the composition further comprisesan anthracycline.

182. The method of item 140, wherein the composition further comprisesdoxorubicin.

183. The method of item 140 wherein the composition further comprisesmitoxantrone.

184. The method of item 140 wherein the composition further comprises afluoropyrimidine.

185. The method of item 140, wherein the composition further comprises5-fluorouracil (5-FU).

186. The method of item 140, wherein the composition further comprises afolic acid antagonist.

187. The method of item 140, wherein the composition further comprisesmethotrexate.

188. The method of item 140, wherein the composition further comprises apodophylotoxin.

189. The method of item 140, wherein the composition further comprisesetoposide.

190. The method of item 140, wherein the composition further comprisescamptothecin.

191. The method of item 140, wherein the composition further comprises ahydroxyurea.

192. The method of item 140, wherein the composition further comprises aplatinum complex.

193. The method of item 140, wherein the composition further comprisescisplatin.

194. The method of item 140 wherein the composition further comprises ananti-thrombotic agent.

195. The method of item 140, wherein the composition further comprises avisualization agent.

196. The method of item 140, wherein the composition further comprises avisualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

197. The method of item 140, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

198. The method of item 140, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, anMRI responsive material.

199. The method of item 140, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, agadolinium chelate.

200. The method of item 140, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, iron,magnesium, manganese, copper, or chromium.

201. The method of item 140, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, ironoxide compound.

202. The method of item 140, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

203. The method of item 140 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

204. The method of item 140 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

205. The method of item 140 wherein the composition further comprises aninflammatory cytokine.

206. The method of item 140 wherein the composition further comprises anagent that stimulates cell proliferation.

207. The method of item 140 wherein the composition further comprises apolymeric carrier.

208. The method of item 140 wherein the composition is in the form of agel, paste, or spray.

209. The method of item 140 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

210. The method of item 140 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

211. The method of item 140 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

212. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

213. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

214. The method of item 140 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

215. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

216. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

217. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

218. The method of item 140 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

219. The method of item 140 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

220. The method of item 140 wherein the agent is delivered from adevice, wherein the device is sterile.

221. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

222. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

223. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

224. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

225. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

226. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

227. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

228. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

229. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

230. The method of item 140 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

231. The method of item 140 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

232. The method of item 140 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

233. The method of item 140 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

234. The method of item 140 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

235. The method of item 140 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

236. The method of item 140 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

237. The method of item 140 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

238. The method of item 140 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

239. The method of item 140 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

240. The method of item 140 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

241. The method of item 140 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

242. The method of item 140 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

243. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

244. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

245. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

246. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

247. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

248. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

249. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

250. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

251. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

252. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

253. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

254. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

255. The method of item 140, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

256. The method of item 140, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

257. The method of item 140, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

258. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with ligament repair.

259. The method of item 258 wherein the agent promotes regeneration.

260. The method of item 258 wherein the agent promotes angiogenesis.

261. The method of item 258 wherein the agent promotes fibroblastmigration.

262. The method of item 258 wherein the agent promotes fibroblastproliferation.

263. The method of item 258 wherein the agent promotes deposition ofextracellular matrix (ECM).

264. The method of item 258 wherein the agent promotes tissueremodeling.

265. The method of item 258 wherein the agent is an arterial vessel wallirritant.

266. The method of item 258 wherein the fibrosing agent is or comprisessilk.

267. The method of item 258 wherein the fibrosing agent is in the formof tufts.

268. The method of item 258 wherein the fibrosing agent is or comprisesmineral particles.

269. The method of item 258 wherein the fibrosing agent is or compriseschitosan.

270. The method of item 258 wherein the fibrosing agent is or comprisespolylysine.

271. The method of item 258 wherein the fibrosing agent is or comprisesfibronectin.

272. The method of item 258 wherein the fibrosing agent is or comprisesbleomycin.

273. The method of item 258 wherein the fibrosing agent is or comprisesCTGF.

274. The method of item 258 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

275. The method of item 258 wherein the fibrosing agent is in the formof a particulate.

276. The method of item 258, wherein the composition comprises apolymer.

277. The method of item 258, wherein the composition comprises apolymer, and the polymer is or comprises, a copolymer.

278. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

279. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

280. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

281. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

282. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

283. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

284. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

285. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

286. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

287. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

288. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

289. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

290. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

291. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

292. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

293. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

294. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

295. The method of item 258, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

296. The method of item 258, wherein the composition further comprises asecond pharmaceutically active agent.

297. The method of item 258, wherein the composition further comprisesan anti-inflammatory agent.

298. The method of item 258, wherein the composition further comprisesan agent that inhibits infection.

299. The method of item 258, wherein the composition further comprisesan anthracycline.

300. The method of item 258, wherein the composition further comprisesdoxorubicin.

301. The method of item 258 wherein the composition further comprisesmitoxantrone.

302. The method of item 258 wherein the composition further comprises afluoropyrimidine.

303. The method of item 258, wherein the composition further comprises5-fluorouracil (5-FU).

304. The method of item 258, wherein the composition further comprises afolic acid antagonist.

305. The method of item 258, wherein the composition further comprisesmethotrexate.

306. The method of item 258, wherein the composition further comprises apodophylotoxin.

307. The method of item 258, wherein the composition further comprisesetoposide.

308. The method of item 258, wherein the composition further comprisescamptothecin.

309. The method of item 258, wherein the composition further comprises ahydroxyurea.

310. The method of item 258, wherein the composition further comprises aplatinum complex.

311. The method of item 258, wherein the composition further comprisescisplatin.

312. The method of item 258 wherein the composition further comprises ananti-thrombotic agent.

313. The method of item 258, wherein the composition further comprises avisualization agent.

314. The method of item 258, wherein the composition further comprises avisualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

315. The method of item 258, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

316. The method of item 258, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, anMRI responsive material.

317. The method of item 258, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, agadolinium chelate.

318. The method of item 258, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, iron,magnesium, manganese, copper, or chromium.

319. The method of item 258, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, ironoxide compound.

320. The method of item 258, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

321. The method of item 258 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

322. The method of item 258 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

323. The method of item 258 wherein the composition further comprises aninflammatory cytokine.

324. The method of item 258 wherein the composition further comprises anagent that stimulates cell proliferation.

325. The method of item 258 wherein the composition further comprises apolymeric carrier.

326. The method of item 258 wherein the composition is in the form of agel, paste, or spray.

327. The method of item 258 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

328. The method of item 258 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

329. The method of item 258 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

330. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

331. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

332. The method of item 258 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

333. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

334. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

335. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

336. The method of item 258 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

337. The method of item 258 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

338. The method of item 258 wherein the agent is delivered from adevice, wherein the device is sterile.

339. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

340. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

341. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

342. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

343. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

344. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

345. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

346. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

347. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

348. The method of item 258 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

349. The method of item 258 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

350. The method of item 258 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

351. The method of item 258 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

352. The method of item 258 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

353. The method of item 258 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

354. The method of item 258 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

355. The method of item 258 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

356. The method of item 258 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

357. The method of item 258 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

358. The method of item 258 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

359. The method of item 258 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

360. The method of item 258 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

361. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

362. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

363. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

364. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

365. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

366. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

367. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

368. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

369. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

370. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

371. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

372. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

373. The method of item 258, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

374. The method of item 258, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

375. The method of item 258, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

376. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with tendon repair.

377. The method of item 376 wherein the agent promotes regeneration.

378. The method of item 376 wherein the agent promotes angiogenesis.

379. The method of item 376 wherein the agent promotes fibroblastmigration.

380. The method of item 376 wherein the agent promotes fibroblastproliferation.

381. The method of item 376 wherein the agent promotes deposition ofextracellular matrix (ECM).

382. The method of item 376 wherein the agent promotes tissueremodeling.

383. The method of item 376 wherein the agent is an arterial vessel wallirritant.

384. The method of item 376 wherein the fibrosing agent is or comprisessilk.

385. The method of item 376 wherein the fibrosing agent is in the formof tufts.

386. The method of item 376 wherein the fibrosing agent is or comprisesmineral particles.

387. The method of item 376 wherein the fibrosing agent is or compriseschitosan.

388. The method of item 376 wherein the fibrosing agent is or comprisespolylysine.

389. The method of item 376 wherein the fibrosing agent is or comprisesfibronectin.

390. The method of item 376 wherein the fibrosing agent is or comprisesbleomycin.

391. The method of item 376 wherein the fibrosing agent is or comprisesCTGF.

392. The method of item 376 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

393. The method of item 376 wherein the fibrosing agent is in the formof a particulate.

394. The method of item 376, wherein the composition comprises apolymer.

395. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

396. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

397. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

398. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

399. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

400. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

401. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

402. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

403. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

404. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

405. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

406. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

407. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

408. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

409. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

410. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

411. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

412. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

413. The method of item 376, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

414. The method of item 376, wherein the composition further comprises asecond pharmaceutically active agent.

415. The method of item 376, wherein the composition further comprisesan anti-inflammatory agent.

416. The method of item 376, wherein the composition further comprisesan agent that inhibits infection.

417. The method of item 376, wherein the composition further comprisesan anthracycline.

418. The method of item 376, wherein the composition further comprisesdoxorubicin.

419. The method of item 376 wherein the composition further comprisesmitoxantrone.

420. The method of item 376 wherein the composition further comprises afluoropyrimidine.

421. The method of item 376, wherein the composition further comprises5-fluorouracil (5-FU).

422. The method of item 376, wherein the composition further comprises afolic acid antagonist.

423. The method of item 376, wherein the composition further comprisesmethotrexate.

424. The method of item 376, wherein the composition further comprises apodophylotoxin.

425. The method of item 376, wherein the composition further comprisesetoposide.

426. The method of item 376, wherein the composition further comprisescamptothecin.

427. The method of item 376, wherein the composition further comprises ahydroxyurea.

428. The method of item 376, wherein the composition further comprises aplatinum complex.

429. The method of item 376, wherein the composition further comprisescisplatin.

430. The method of item 376 wherein the composition further comprises ananti-thrombotic agent.

431. The method of item 376, wherein the composition further comprises avisualization agent.

432. The method of item 376, wherein the composition further comprises avisualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

433. The method of item 376, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

434. The method of item 376, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, anMRI responsive material.

435. The method of item 376, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, agadolinium chelate.

436. The method of item 376, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, iron,magnesium, manganese, copper, or chromium.

437. The method of item 376, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, ironoxide compound.

438. The method of item 376, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

439. The method of item 376 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

440. The method of item 376 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

441. The method of item 376 wherein the composition further comprises aninflammatory cytokine.

442. The method of item 376 wherein the composition further comprises anagent that stimulates cell proliferation.

443. The method of item 376 wherein the composition further comprises apolymeric carrier.

444. The method of item 376 wherein the composition is in the form of agel, paste, or spray.

445. The method of item 376 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

446. The method of item 376 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

447. The method of item 376 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

448. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

449. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

450. The method of item 376 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

451. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

452. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

453. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

454. The method of item 376 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

455. The method of item 376 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

456. The method of item 376 wherein the agent is delivered from adevice, wherein the device is sterile.

457. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

458. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

459. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

460. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

461. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

462. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

463. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

464. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

465. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

466. The method of item 376 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

467. The method of item 376 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

468. The method of item 376 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

469. The method of item 376 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

470. The method of item 376 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

471. The method of item 376 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

472. The method of item 376 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

473. The method of item 376 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

474. The method of item 376 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

475. The method of item 376 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

476. The method of item 376 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

477. The method of item 376 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

478. The method of item 376 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

479. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

480. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

481. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

482. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

483. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

484. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

485. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

486. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

487. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

488. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

489. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

490. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

491. The method of item 376, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

492. The method of item 376, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

493. The method of item 376, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

494. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with hernia repair.

495. The method of item 494 wherein the agent promotes regeneration.

496. The method of item 494 wherein the agent promotes angiogenesis.

497. The method of item 494 wherein the agent promotes fibroblastmigration.

498. The method of item 494 wherein the agent promotes fibroblastproliferation.

499. The method of item 494 wherein the agent promotes deposition ofextracellular matrix (ECM).

500. The method of item 494 wherein the agent promotes tissueremodeling.

501. The method of item 494 wherein the agent is an arterial vessel wallirritant.

502. The method of item 494 wherein the fibrosing agent is or comprisessilk.

503. The method of item 494 wherein the fibrosing agent is in the formof tufts.

504. The method of item 494 wherein the fibrosing agent is or comprisesmineral particles.

505. The method of item 494 wherein the fibrosing agent is or compriseschitosan.

506. The method of item 494 wherein the fibrosing agent is or comprisespolylysine.

507. The method of item 494 wherein the fibrosing agent is or comprisesfibronectin.

508. The method of item 494 wherein the fibrosing agent is or comprisesbleomycin.

509. The method of item 494 wherein the fibrosing agent is or comprisesCTGF.

510. The method of item 494 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

511. The method of item 494 wherein the fibrosing agent is in the formof a particulate.

512. The method of item 494, wherein the composition comprises apolymer.

513. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

514. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

515. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

516. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

517. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

518. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

519. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

520. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

521. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

522. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

523. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

524. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

525. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

526. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

527. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

528. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

529. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

530. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

531. The method of item 494, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

532. The method of item 494, wherein the composition further comprises asecond pharmaceutically active agent.

533. The method of item 494, wherein the composition further comprisesan anti-inflammatory agent.

534. The method of item 494, wherein the composition further comprisesan agent that inhibits infection.

535. The method of item 494, wherein the composition further comprisesan anthracycline.

536. The method of item 494, wherein the composition further comprisesdoxorubicin.

537. The method of item 494 wherein the composition further comprisesmitoxantrone.

538. The method of item 494 wherein the composition further comprises afluoropyrimidine.

539. The method of item 494, wherein the composition further comprises5-fluorouracil (5-FU).

540. The method of item 494, wherein the composition further comprises afolic acid antagonist.

541. The method of item 494, wherein the composition further comprisesmethotrexate.

542. The method of item 494, wherein the composition further comprises apodophylotoxin.

543. The method of item 494, wherein the composition further comprisesetoposide.

544. The method of item 494, wherein the composition further comprisescamptothecin.

545. The method of item 494, wherein the composition further comprises ahydroxyurea.

546. The method of item 494, wherein the composition further comprises aplatinum complex.

547. The method of item 494, wherein the composition further comprisescisplatin.

548. The method of item 494 wherein the composition further comprises ananti-thrombotic agent.

549. The method of item 494, wherein the composition further comprises avisualization agent.

550. The method of item 494, wherein the composition further comprises avisualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

551. The method of item 494, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

552. The method of item 494, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, anMRI responsive material.

553. The method of item 494, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, agadolinium chelate.

554. The method of item 494, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, iron,magnesium, manganese, copper, or chromium.

555. The method of item 494, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, ironoxide compound.

556. The method of item 494, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

557. The method of item 494 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

558. The method of item 494 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

559. The method of item 494 wherein the composition further comprises aninflammatory cytokine.

560. The method of item 494 wherein the composition further comprises anagent that stimulates cell proliferation.

561. The method of item 494 wherein the composition further comprises apolymeric carrier.

562. The method of item 494 wherein the composition is in the form of agel, paste, or spray.

563. The method of item 494 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

564. The method of item 494 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

565. The method of item 494 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

566. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

567. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

568. The method of item 494 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

569. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

570. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

571. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

572. The method of item 494 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

573. The method of item 494 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

574. The method of item 494 wherein the agent is delivered from adevice, wherein the device is sterile.

575. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

576. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

577. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

578. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

579. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

580. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

581. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

582. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

583. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

584. The method of item 494 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

585. The method of item 494 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

586. The method of item 494 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

587. The method of item 494 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

588. The method of item 494 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

589. The method of item 494 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

590. The method of item 494 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

591. The method of item 494 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

592. The method of item 494 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

593. The method of item 494 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

594. The method of item 494 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

595. The method of item 494 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

596. The method of item 494 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

597. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

598. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

599. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

600. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

601. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

602. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

603. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

604. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

605. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

606. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

607. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

608. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

609. The method of item 494, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

610. The method of item 494, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

611. The method of item 494, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

612. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with pulmonary sealing.

613. The method of item 612 wherein the agent promotes regeneration.

614. The method of item 612 wherein the agent promotes angiogenesis.

615. The method of item 612 wherein the agent promotes fibroblastmigration.

616. The method of item 612 wherein the agent promotes fibroblastproliferation.

617. The method of item 612 wherein the agent promotes deposition ofextracellular matrix (ECM).

618. The method of item 612 wherein the agent promotes tissueremodeling.

619. The method of item 612 wherein the agent is an arterial vessel wallirritant.

620. The method of item 612 wherein the fibrosing agent is or comprisessilk.

621. The method of item 612 wherein the fibrosing agent is in the formof tufts.

622. The method of item 612 wherein the fibrosing agent is or comprisesmineral particles.

623. The method of item 612 wherein the fibrosing agent is or compriseschitosan.

624. The method of item 612 wherein the fibrosing agent is or comprisespolylysine.

625. The method of item 612 wherein the fibrosing agent is or comprisesfibronectin.

626. The method of item 612 wherein the fibrosing agent is or comprisesbleomycin.

627. The method of item 612 wherein the fibrosing agent is or comprisesCTGF.

628. The method of item 612 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

629. The method of item 612 wherein the fibrosing agent is in the formof a particulate.

630. The method of item 612, wherein the composition comprises apolymer.

631. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

632. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

633. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

634. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

635. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

636. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

637. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

638. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

639. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

640. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

641. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

642. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

643. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

644. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

645. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

646. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

647. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

648. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

649. The method of item 612, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

650. The method of item 612, wherein the composition further comprises asecond pharmaceutically active agent.

651. The method of item 612, wherein the composition further comprisesan anti-inflammatory agent.

652. The method of item 612, wherein the composition further comprisesan agent that inhibits infection.

653. The method of item 612, wherein the composition further comprisesan anthracycline.

654. The method of item 612, wherein the composition further comprisesdoxorubicin.

655. The method of item 612 wherein the composition further comprisesmitoxantrone.

656. The method of item 612 wherein the composition further comprises afluoropyrimidine.

657. The method of item 612, wherein the composition further comprises5-fluorouracil (5-FU).

658. The method of item 612, wherein the composition further comprises afolic acid antagonist.

659. The method of item 612, wherein the composition further comprisesmethotrexate.

660. The method of item 612, wherein the composition further comprises apodophylotoxin.

661. The method of item 612, wherein the composition further comprisesetoposide.

662. The method of item 612, wherein the composition further comprisescamptothecin.

663. The method of item 612, wherein the composition further comprises ahydroxyurea.

664. The method of item 612, wherein the composition further comprises aplatinum complex.

665. The method of item 612, wherein the composition further comprisescisplatin.

666. The method of item 612 wherein the composition further comprises ananti-thrombotic agent.

667. The method of item 612, wherein the composition further comprises avisualization agent.

668. The method of item 612, wherein the composition further comprises avisualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

669. The method of item 612, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

670. The method of item 612, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, anMRI responsive material.

671. The method of item 612, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, agadolinium chelate.

672. The method of item 612, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, iron,magnesium, manganese, copper, or chromium.

673. The method of item 612, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, ironoxide compound.

674. The method of item 612, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

675. The method of item 612 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

676. The method of item 612 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

677. The method of item 612 wherein the composition further comprises aninflammatory cytokine.

678. The method of item 612 wherein the composition further comprises anagent that stimulates cell proliferation.

679. The method of item 612 wherein the composition further comprises apolymeric carrier.

680. The method of item 612 wherein the composition is in the form of agel, paste, or spray.

681. The method of item 612 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

682. The method of item 612 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

683. The method of item 612 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

684. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

685. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

686. The method of item 612 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

687. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

688. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

689. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

690. The method of item 612 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

691. The method of item 612 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

692. The method of item 612 wherein the agent is delivered from adevice, wherein the device is sterile.

693. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

694. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

695. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

696. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

697. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

698. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

699. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

700. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

701. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

702. The method of item 612 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

703. The method of item 612 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

704. The method of item 612 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

705. The method of item 612 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

706. The method of item 612 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

707. The method of item 612 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

708. The method of item 612 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

709. The method of item 612 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

710. The method of item 612 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

711. The method of item 612 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

712. The method of item 612 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

713. The method of item 612 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

714. The method of item 612 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

715. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

716. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

717. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

718. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

719. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

720. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

721. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

722. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

723. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

724. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

725. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

726. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

727. The method of item 612, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

728. The method of item 612, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

729. The method of item 612, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

730. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with treatment or prevention of an aneurysm.

731. The method of item 730 wherein the agent promotes regeneration.

732. The method of item 730 wherein the agent promotes angiogenesis.

733. The method of item 730 wherein the agent promotes fibroblastmigration.

734. The method of item 730 wherein the agent promotes fibroblastproliferation.

735. The method of item 730 wherein the agent promotes deposition ofextracellular matrix (ECM).

736. The method of item 730 wherein the agent promotes tissueremodeling.

737. The method of item 730 wherein the agent is an arterial vessel wallirritant.

738. The method of item 730 wherein the fibrosing agent is or comprisessilk.

739. The method of item 730 wherein the fibrosing agent is in the formof tufts.

740. The method of item 730 wherein the fibrosing agent is or comprisesmineral particles.

741. The method of item 730 wherein the fibrosing agent is or compriseschitosan.

742. The method of item 730 wherein the fibrosing agent is or comprisespolylysine.

743. The method of item 730 wherein the fibrosing agent is or comprisesfibronectin.

744. The method of item 730 wherein the fibrosing agent is or comprisesbleomycin.

745. The method of item 730 wherein the fibrosing agent is or comprisesCTGF.

746. The method of item 730 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

747. The method of item 730 wherein the fibrosing agent is in the formof a particulate.

748. The method of item 730, wherein the composition comprises apolymer.

749. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

750. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

751. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

752. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

753. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

754. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

755. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

756. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

757. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

758. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

759. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

760. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

761. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

762. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

763. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

764. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

765. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

766. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

767. The method of item 730, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

768. The method of item 730, wherein the composition further comprises asecond pharmaceutically active agent.

769. The method of item 730, wherein the composition further comprisesan anti-inflammatory agent.

770. The method of item 730, wherein the composition further comprisesan agent that inhibits infection.

771. The method of item 730, wherein the composition further comprisesan anthracycline.

772. The method of item 730, wherein the composition further comprisesdoxorubicin.

773. The method of item 730 wherein the composition further comprisesmitoxantrone.

774. The method of item 730 wherein the composition further comprises afluoropyrimidine.

775. The method of item 730, wherein the composition further comprises5-fluorouracil (5-FU).

776. The method of item 730, wherein the composition further comprises afolic acid antagonist.

777. The method of item 730, wherein the composition further comprisesmethotrexate.

778. The method of item 730, wherein the composition further comprises apodophylotoxin.

779. The method of item 730, wherein the composition further comprisesetoposide.

780. The method of item 730, wherein the composition further comprisescamptothecin.

781. The method of item 730, wherein the composition further comprises ahydroxyurea.

782. The method of item 730, wherein the composition further comprises aplatinum complex.

783. The method of item 730, wherein the composition further comprisescisplatin.

784. The method of item 730 wherein the composition further comprises ananti-thrombotic agent.

785. The method of item 730, wherein the composition further comprises avisualization agent.

786. The method of item 730, wherein the composition further comprises avisualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

787. The method of item 730, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

788. The method of item 730, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, anMRI responsive material.

789. The method of item 730, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, agadolinium chelate.

790. The method of item 730, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, iron,magnesium, manganese, copper, or chromium.

791. The method of item 730, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, ironoxide compound.

792. The method of item 730, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

793. The method of item 730 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

794. The method of item 730 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

795. The method of item 730 wherein the composition further comprises aninflammatory cytokine.

796. The method of item 730 wherein the composition further comprises anagent that stimulates cell proliferation.

797. The method of item 730 wherein the composition further comprises apolymeric carrier.

798. The method of item 730 wherein the composition is in the form of agel, paste, or spray.

799. The method of item 730 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

800. The method of item 730 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

801. The method of item 730 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

802. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

803. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

804. The method of item 730 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

805. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

806. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

807. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

808. The method of item 730 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

809. The method of item 730 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

810. The method of item 730 wherein the agent is delivered from adevice, wherein the device is sterile.

811. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

812. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

813. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

814. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

815. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

816. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

817. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

818. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

819. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

820. The method of item 730 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

821. The method of item 730 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

822. The method of item 730 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

823. The method of item 730 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

824. The method of item 730 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

825. The method of item 730 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

826. The method of item 730 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

827. The method of item 730 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

828. The method of item 730 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

829. The method of item 730 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

830. The method of item 730 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

831. The method of item 730 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

832. The method of item 730 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

833. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

834. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

835. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

836. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

837. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

838. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

839. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

840. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

841. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

842. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

843. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

844. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

845. The method of item 730, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

846. The method of item 730, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

847. The method of item 730, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

848. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with embolization.

849. The method of item 848 wherein the agent promotes regeneration.

850. The method of item 848 wherein the agent promotes angiogenesis.

851. The method of item 848 wherein the agent promotes fibroblastmigration.

852. The method of item 848 wherein the agent promotes fibroblastproliferation.

853. The method of item 848 wherein the agent promotes deposition ofextracellular matrix (ECM).

854. The method of item 848 wherein the agent promotes tissueremodeling.

855. The method of item 848 wherein the agent is an arterial vessel wallirritant.

856. The method of item 848 wherein the fibrosing agent is or comprisessilk.

857. The method of item 848 wherein the fibrosing agent is in the formof tufts.

858. The method of item 848 wherein the fibrosing agent is or comprisesmineral particles.

859. The method of item 848 wherein the fibrosing agent is or compriseschitosan.

860. The method of item 848 wherein the fibrosing agent is or comprisespolylysine.

861. The method of item 848 wherein the fibrosing agent is or comprisesfibronectin.

862. The method of item 848 wherein the fibrosing agent is or comprisesbleomycin.

863. The method of item 848 wherein the fibrosing agent is or comprisesCTGF.

864. The method of item 848 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

865. The method of item 848 wherein the fibrosing agent is in the formof a particulate.

866. The method of item 848, wherein the composition comprises apolymer.

867. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

868. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

869. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

870. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

871. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

872. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

873. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

874. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

875. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

876. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

877. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

878. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

879. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

880. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

881. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

882. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

883. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

884. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

885. The method of item 848, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

886. The method of item 848, wherein the composition further comprises asecond pharmaceutically active agent.

887. The method of item 848, wherein the composition further comprisesan anti-inflammatory agent.

888. The method of item 848, wherein the composition further comprisesan agent that inhibits infection.

889. The method of item 848, wherein the composition further comprisesan anthracycline.

890. The method of item 848, wherein the composition further comprisesdoxorubicin.

891. The method of item 848 wherein the composition further comprisesmitoxantrone.

892. The method of item 848 wherein the composition further comprises afluoropyrimidine.

893. The method of item 848, wherein the composition further comprises5-fluorouracil (5-FU).

894. The method of item 848, wherein the composition further comprises afolic acid antagonist.

895. The method of item 848, wherein the composition further comprisesmethotrexate.

896. The method of item 848, wherein the composition further comprises apodophylotoxin.

897. The method of item 848, wherein the composition further comprisesetoposide.

898. The method of item 848, wherein the composition further comprisescamptothecin.

899. The method of item 848, wherein the composition further comprises ahydroxyurea.

900. The method of item 848, wherein the composition further comprises aplatinum complex.

901. The method of item 848, wherein the composition further comprisescisplatin.

902. The method of item 848 wherein the composition further comprises ananti-thrombotic agent.

903. The method of item 848, wherein the composition further comprises avisualization agent.

904. The method of item 848, wherein the composition further comprises avisualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

905. The method of item 848, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

906. The method of item 848, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, anMRI responsive material.

907. The method of item 848, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, agadolinium chelate.

908. The method of item 848, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, iron,magnesium, manganese, copper, or chromium.

909. The method of item 848, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, ironoxide compound.

910. The method of item 848, wherein the composition further comprises avisualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

911. The method of item 848 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

912. The method of item 848 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

913. The method of item 848 wherein the composition further comprises aninflammatory cytokine.

914. The method of item 848 wherein the composition further comprises anagent that stimulates cell proliferation.

915. The method of item 848 wherein the composition further comprises apolymeric carrier.

916. The method of item 848 wherein the composition is in the form of agel, paste, or spray.

917. The method of item 848 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

918. The method of item 848 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

919. The method of item 848 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

920. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

921. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

922. The method of item 848 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

923. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

924. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

925. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

926. The method of item 848 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

927. The method of item 848 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

928. The method of item 848 wherein the agent is delivered from adevice, wherein the device is sterile.

929. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

930. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

931. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

932. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

933. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

934. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

935. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

936. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

937. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

938. The method of item 848 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

939. The method of item 848 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

940. The method of item 848 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

941. The method of item 848 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

942. The method of item 848 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

943, The method of item 848 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

944. The method of item 848 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

945. The method of item 848 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

946. The method of item 848 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

947. The method of item 848 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

948. The method of item 848 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

949. The method of item 848 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

950. The method of item 848 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

951. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

952. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

953. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

954. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

955. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

956. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

957. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

958. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

959. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

960. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

961. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

962. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

963. The method of item 848, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

964. The method of item 848, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

965. The method of item 848, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

966. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with a fibrotic response between the patient and asoft palate implant.

967. The method of item 966 wherein the agent promotes regeneration.

968. The method of item 966 wherein the agent promotes angiogenesis.

969. The method of item 966 wherein the agent promotes fibroblastmigration.

970. The method of item 966 wherein the agent promotes fibroblastproliferation.

971. The method of item 966 wherein the agent promotes deposition ofextracellular matrix (ECM).

972. The method of item 966 wherein the agent promotes tissueremodeling.

973. The method of item 966 wherein the agent is an arterial vessel wallirritant.

974. The method of item 966 wherein the fibrosing agent is or comprisessilk.

975. The method of item 966 wherein the fibrosing agent is in the formof tufts.

976. The method of item 966 wherein the fibrosing agent is or comprisesmineral particles.

977. The method of item 966 wherein the fibrosing agent is or compriseschitosan.

978. The method of item 966 wherein the fibrosing agent is or comprisespolylysine.

979. The method of item 966 wherein the fibrosing agent is or comprisesfibronectin.

980. The method of item 966 wherein the fibrosing agent is or comprisesbleomycin.

981. The method of item 966 wherein the fibrosing agent is or comprisesCTGF.

982. The method of item 966 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

983. The method of item 966 wherein the fibrosing agent is in the formof a particulate.

984. The method of item 966, wherein the composition comprises apolymer.

985. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

986. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

987. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

988. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

989. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

990. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

991. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

992. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

993. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

994. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

995. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

996. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

997. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

998. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

999. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

1000. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

1001. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

1002. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

1003. The method of item 966, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

1004. The method of item 966, wherein the composition further comprisesa second pharmaceutically active agent.

1005. The method of item 966, wherein the composition further comprisesan anti-inflammatory agent.

1006. The method of item 966, wherein the composition further comprisesan agent that inhibits infection.

1007. The method of item 966, wherein the composition further comprisesan anthracycline.

1008. The method of item 966, wherein the composition further comprisesdoxorubicin.

1009. The method of item 966 wherein the composition further comprisesmitoxantrone.

1010. The method of item 966 wherein the composition further comprises afluoropyrimidine.

1011. The method of item 966, wherein the composition further comprises5-fluorouracil (5-FU).

1012. The method of item 966, wherein the composition further comprisesa folic acid antagonist.

1013. The method of item 966, wherein the composition further comprisesmethotrexate.

1014. The method of item 966, wherein the composition further comprisesa podophylotoxin.

1015. The method of item 966, wherein the composition further comprisesetoposide.

1016. The method of item 966, wherein the composition further comprisescamptothecin.

1017. The method of item 966, wherein the composition further comprisesa hydroxyurea.

1018. The method of item 966, wherein the composition further comprisesa platinum complex.

1019. The method of item 966, wherein the composition further comprisescisplatin.

1020. The method of item 966 wherein the composition further comprisesan anti-thrombotic agent.

1021. The method of item 966, wherein the composition further comprisesa visualization agent.

1022. The method of item 966, wherein the composition further comprisesa visualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

1023. The method of item 966, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

1024. The method of item 966, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, anMRI responsive material.

1025. The method of item 966, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, agadolinium chelate.

1026. The method of item 966, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron, magnesium, manganese, copper, or chromium.

1027. The method of item 966, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron oxide compound.

1028. The method of item 966, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

1029. The method of item 966 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

1030. The method of item 966 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

1031. The method of item 966 wherein the composition further comprisesan inflammatory cytokine.

1032. The method of item 966 wherein the composition further comprisesan agent that stimulates cell proliferation.

1033. The method of item 966 wherein the composition further comprises apolymeric carrier.

1034. The method of item 966 wherein the composition is in the form of agel, paste, or spray.

1035. The method of item 966 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

1036. The method of item 966 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

1037. The method of item 966 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

1038. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

1039. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

1040. The method of item 966 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

1041. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

1042. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

1043. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

1044. The method of item 966 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

1045. The method of item 966 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

1046. The method of item 966 wherein the agent is delivered from adevice, wherein the device is sterile.

1047. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

1048. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

1049. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

1050. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

1051. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

1052. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

1053. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

1054. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

1055. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

1056. The method of item 966 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

1057. The method of item 966 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

1058. The method of item 966 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

1059. The method of item 966 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

1060. The method of item 966 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

1061. The method of item 966 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

1062. The method of item 966 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

1063. The method of item 966 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

1064. The method of item 966 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1065. The method of item 966 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1066. The method of item 966 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1067. The method of item 966 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

1068. The method of item 966 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1069. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

1070. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

1071. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

1072. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

1073. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

1074. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

1075. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

1076. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

1077. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

1078. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

1079. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

1080. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

1081. The method of item 966, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

1082. The method of item 966, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

1083. The method of item 966, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

1084. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with treatment for obesity.

1085. The method of item 1084 wherein the agent promotes regeneration.

1086. The method of item 1084 wherein the agent promotes angiogenesis.

1087. The method of item 1084 wherein the agent promotes fibroblastmigration.

1088. The method of item 1084 wherein the agent promotes fibroblastproliferation.

1089. The method of item 1084 wherein the agent promotes deposition ofextracellular matrix (ECM).

1090. The method of item 1084 wherein the agent promotes tissueremodeling.

1091. The method of item 1084 wherein the agent is an arterial vesselwall irritant.

1092. The method of item 1084 wherein the fibrosing agent is orcomprises silk.

1093. The method of item 1084 wherein the fibrosing agent is in the formof tufts.

1094. The method of item 1084 wherein the fibrosing agent is orcomprises mineral particles.

1095. The method of item 1084 wherein the fibrosing agent is orcomprises chitosan.

1096. The method of item 1084 wherein the fibrosing agent is orcomprises polylysine.

1097. The method of item 1084 wherein the fibrosing agent is orcomprises fibronectin.

1098. The method of item 1084 wherein the fibrosing agent is orcomprises bleomycin.

1099. The method of item 1084 wherein the fibrosing agent is orcomprises CTGF.

1100. The method of item 1084 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

1101. The method of item 1084 wherein the fibrosing agent is in the formof a particulate.

1102. The method of item 1084, wherein the composition comprises apolymer.

1103. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

1104. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

1105. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

1106. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

1107. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

1108. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

1109. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

1110. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

1111. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

1112. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

1113. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

1114. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

1115. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

1116. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

1117. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

1118. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

1119. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

1120. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

1121. The method of item 1084, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

1122. The method of item 1084, wherein the composition further comprisesa second pharmaceutically active agent.

1123. The method of item 1084, wherein the composition further comprisesan anti-inflammatory agent.

1124. The method of item 1084, wherein the composition further comprisesan agent that inhibits infection.

1125. The method of item 1084, wherein the composition further comprisesan anthracycline.

1126. The method of item 1084, wherein the composition further comprisesdoxorubicin.

1127. The method of item 1084 wherein the composition further comprisesmitoxantrone.

1128. The method of item 1084 wherein the composition further comprisesa fluoropyrimidine.

1129. The method of item 1084, wherein the composition further comprises5-fluorouracil (5-FU).

1130. The method of item 1084, wherein the composition further comprisesa folic acid antagonist.

1131. The method of item 1084, wherein the composition further comprisesmethotrexate.

1132. The method of item 1084, wherein the composition further comprisesa podophylotoxin.

1133. The method of item 1084, wherein the composition further comprisesetoposide.

1134. The method of item 1084, wherein the composition further comprisescamptothecin.

1135. The method of item 1084, wherein the composition further comprisesa hydroxyurea.

1136. The method of item 1084, wherein the composition further comprisesa platinum complex.

1137. The method of item 1084, wherein the composition further comprisescisplatin.

1138. The method of item 1084 wherein the composition further comprisesan anti-thrombotic agent.

1139. The method of item 1084, wherein the composition further comprisesa visualization agent.

1140. The method of item 1084, wherein the composition further comprisesa visualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

1141. The method of item 1084, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

1142. The method of item 1084, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, anMRI responsive material.

1143. The method of item 1084, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, agadolinium chelate.

1144. The method of item 1084, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron, magnesium, manganese, copper, or chromium.

1145. The method of item 1084, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron oxide compound.

1146. The method of item 1084, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

1147. The method of item 1084 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

1148. The method of item 1084 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

1149. The method of item 1084 wherein the composition further comprisesan inflammatory cytokine.

1150. The method of item 1084 wherein the composition further comprisesan agent that stimulates cell proliferation.

1151. The method of item 1084 wherein the composition further comprisesa polymeric carrier.

1152. The method of item 1084 wherein the composition is in the form ofa gel, paste, or spray.

1153. The method of item 1084 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

1154. The method of item 1084 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

1155. The method of item 1084 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

1156. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

1157. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

1158. The method of item 1084 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

1159. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

1160. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

1161. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

1162. The method of item 1084 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

1163. The method of item 1084 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

1164. The method of item 1084 wherein the agent is delivered from adevice, wherein the device is sterile.

1165. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

1166. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

1167. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

1168. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

1169. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

1170. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

1171. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

1172. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

1173. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

1174. The method of item 1084 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

1175. The method of item 1084 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

1176. The method of item 1084 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

1177. The method of item 1084 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

1178. The method of item 1084 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

1179. The method of item 1084 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

1180. The method of item 1084 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

1181. The method of item 1084 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

1182. The method of item 1084 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1183. The method of item 1084 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1184. The method of item 1084 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1185. The method of item 1084 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

1186. The method of item 1084 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1187. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

1188. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

1189. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

1190. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

1191. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

1192. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

1193. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

1194. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

1195. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

1196. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

1197. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

1198. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

1199. The method of item 1084, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

1200. The method of item 1084, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

1201. The method of item 1084, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

1202. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with treatment for GERD.

1203. The method of item 1202 wherein the agent promotes regeneration.

1204. The method of item 1202 wherein the agent promotes angiogenesis.

1205. The method of item 1202 wherein the agent promotes fibroblastmigration.

1206. The method of item 1202 wherein the agent promotes fibroblastproliferation.

1207. The method of item 1202 wherein the agent promotes deposition ofextracellular matrix (ECM).

1208. The method of item 1202 wherein the agent promotes tissueremodeling.

1209. The method of item 1202 wherein the agent is an arterial vesselwall irritant.

1210. The method of item 1202 wherein the fibrosing agent is orcomprises silk.

1211. The method of item 1202 wherein the fibrosing agent is in the formof tufts.

1212. The method of item 1202 wherein the fibrosing agent is orcomprises mineral particles.

1213. The method of item 1202 wherein the fibrosing agent is orcomprises chitosan.

1214. The method of item 1202 wherein the fibrosing agent is orcomprises polylysine.

1215. The method of item 1202 wherein the fibrosing agent is orcomprises fibronectin.

1216. The method of item 1202 wherein the fibrosing agent is orcomprises bleomycin.

1217. The method of item 1202 wherein the fibrosing agent is orcomprises CTGF.

1218. The method of item 1202 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

1219. The method of item 1202 wherein the fibrosing agent is in the formof a particulate.

1220. The method of item 1202, wherein the composition comprises apolymer.

1221. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

1222. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

1223. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

1224. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

1225. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

1226. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

1227. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

1228. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

1229. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

1230. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

1231. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

1232. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

1233. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

1234. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

1235. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

1236. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

1237. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

1238. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

1239. The method of item 1202, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

1240. The method of item 1202, wherein the composition further comprisesa second pharmaceutically active agent.

1241. The method of item 1202, wherein the composition further comprisesan anti-inflammatory agent.

1242. The method of item 1202, wherein the composition further comprisesan agent that inhibits infection.

1243. The method of item 1202, wherein the composition further comprisesan anthracycline.

1244. The method of item 1202, wherein the composition further comprisesdoxorubicin.

1245. The method of item 1202 wherein the composition further comprisesmitoxantrone.

1246. The method of item 1202 wherein the composition further comprisesa fluoropyrimidine.

1247. The method of item 1202, wherein the composition further comprises5-fluorouracil (5-FU).

1248. The method of item 1202, wherein the composition further comprisesa folic acid antagonist.

1249. The method of item 1202, wherein the composition further comprisesmethotrexate.

1250. The method of item 1202, wherein the composition further comprisesa podophylotoxin.

1251. The method of item 1202, wherein the composition further comprisesetoposide.

1252. The method of item 1202, wherein the composition further comprisescamptothecin.

1253. The method of item 1202, wherein the composition further comprisesa hydroxyurea.

1254. The method of item 1202, wherein the composition further comprisesa platinum complex.

1255. The method of item 1202, wherein the composition further comprisescisplatin.

1256. The method of item 1202 wherein the composition further comprisesan anti-thrombotic agent.

1257. The method of item 1202, wherein the composition further comprisesa visualization agent.

1258. The method of item 1202, wherein the composition further comprisesa visualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

1259. The method of item 1202, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

1260. The method of item 1202, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, anMRI responsive material.

1261. The method of item 1202, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, agadolinium chelate.

1262. The method of item 1202, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron, magnesium, manganese, copper, or chromium.

1263. The method of item 1202, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron oxide compound.

1264. The method of item 1202, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

1265. The method of item 1202 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

1266. The method of item 1202 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

1267. The method of item 1202 wherein the composition further comprisesan inflammatory cytokine.

1268. The method of item 1202 wherein the composition further comprisesan agent that stimulates cell proliferation.

1269. The method of item 1202 wherein the composition further comprisesa polymeric carrier.

1270. The method of item 1202 wherein the composition is in the form ofa gel, paste, or spray.

1271. The method of item 1202 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

1272. The method of item 1202 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

1273. The method of item 1202 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

1274. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

1275. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

1276. The method of item 1202 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

1277. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

1278. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

1279. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

1280. The method of item 1202 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

1281. The method of item 1202 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

1282. The method of item 1202 wherein the agent is delivered from adevice, wherein the device is sterile.

1283. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

1284. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

1285. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

1286. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

1287. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

1288. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

1289. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

1290. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

1291. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

1292. The method of item 1202 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

1293. The method of item 1202 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

1294. The method of item 1202 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

1295. The method of item 1202 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

1296. The method of item 1202 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

1297. The method of item 1202 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

1298. The method of item 1202 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

1299. The method of item 1202 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

1300. The method of item 1202 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1301. The method of item 1202 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1302. The method of item 1202 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1303. The method of item 1202 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

1304. The method of item 1202 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1305. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

1306. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

1307. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

1308. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

1309. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

1310. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

1311. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

1312. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

1313. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

1314. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

1315. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

1316. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

1317. The method of item 1202, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

1318. The method of item 1202, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

1319. The method of item 1202, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

1320. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with treatment or prevention of fecalincontinence.

1321. The method of item 1320 wherein the agent promotes regeneration.

1322. The method of item 1320 wherein the agent promotes angiogenesis.

1323. The method of item 1320 wherein the agent promotes fibroblastmigration.

1324. The method of item 1320 wherein the agent promotes fibroblastproliferation.

1325. The method of item 1320 wherein the agent promotes deposition ofextracellular matrix (ECM).

1326. The method of item 1320 wherein the agent promotes tissueremodeling.

1327. The method of item 1320 wherein the agent is an arterial vesselwall irritant.

1328. The method of item 1320 wherein the fibrosing agent is orcomprises silk.

1329. The method of item 1320 wherein the fibrosing agent is in the formof tufts.

1330. The method of item 1320 wherein the fibrosing agent is orcomprises mineral particles.

1331. The method of item 1320 wherein the fibrosing agent is orcomprises chitosan.

1332. The method of item 1320 wherein the fibrosing agent is orcomprises polylysine.

1333. The method of item 1320 wherein the fibrosing agent is orcomprises fibronectin.

1334. The method of item 1320 wherein the fibrosing agent is orcomprises bleomycin.

1335. The method of item 1320 wherein the fibrosing agent is orcomprises CTGF.

1336. The method of item 1320 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

1337. The method of item 1320 wherein the fibrosing agent is in the formof a particulate.

1338. The method of item 1320, wherein the composition comprises apolymer.

1339. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

1340. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

1341. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

1342. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

1343. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

1344. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

1345. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

1346. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

1347. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

1348. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

1349. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

1350. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

1351. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

1352. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

1353. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

1354. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

1355. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

1356. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

1357. The method of item 1320, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

1358. The method of item 1320, wherein the composition further comprisesa second pharmaceutically active agent.

1359. The method of item 1320, wherein the composition further comprisesan anti-inflammatory agent.

1360. The method of item 1320, wherein the composition further comprisesan agent that inhibits infection.

1361. The method of item 1320, wherein the composition further comprisesan anthracycline.

1362. The method of item 1320, wherein the composition further comprisesdoxorubicin.

1363. The method of item 1320 wherein the composition further comprisesmitoxantrone.

1364. The method of item 1320 wherein the composition further comprisesa fluoropyrimidine.

1365. The method of item 1320, wherein the composition further comprises5-fluorouracil (5-FU).

1366. The method of item 1320, wherein the composition further comprisesa folic acid antagonist.

1367. The method of item 1320, wherein the composition further comprisesmethotrexate.

1368. The method of item 1320, wherein the composition further comprisesa podophylotoxin.

1369. The method of item 1320, wherein the composition further comprisesetoposide.

1370. The method of item 1320, wherein the composition further comprisescamptothecin.

1371. The method of item 1320, wherein the composition further comprisesa hydroxyurea.

1372. The method of item 1320, wherein the composition further comprisesa platinum complex.

1373. The method of item 1320, wherein the composition further comprisescisplatin.

1374. The method of item 1320 wherein the composition further comprisesan anti-thrombotic agent.

1375. The method of item 1320, wherein the composition further comprisesa visualization agent.

1376. The method of item 1320, wherein the composition further comprisesa visualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

1377. The method of item 1320, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

1378. The method of item 1320, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, anMRI responsive material.

1379. The method of item 1320, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, agadolinium chelate.

1380. The method of item 1320, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron, magnesium, manganese, copper, or chromium.

1381. The method of item 1320, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron oxide compound.

1382. The method of item 1320, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

1383. The method of item 1320 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

1384. The method of item 1320 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

1385. The method of item 1320 wherein the composition further comprisesan inflammatory cytokine.

1386. The method of item 1320 wherein the composition further comprisesan agent that stimulates cell proliferation.

1387. The method of item 1320 wherein the composition further comprisesa polymeric carrier.

1388. The method of item 1320 wherein the composition is in the form ofa gel, paste, or spray.

1389. The method of item 1320 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

1390. The method of item 1320 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

1391. The method of item 1320 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

1392. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

1393. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

1394. The method of item 1320 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

1395. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

1396. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

1397. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

1398. The method of item 1320 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

1399. The method of item 1320 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

1400. The method of item 1320 wherein the agent is delivered from adevice, wherein the device is sterile.

1401. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

1402. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

1403. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

1404. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

1405. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

1406. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

1407. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

1408. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

1409. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

1410. The method of item 1320 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

1411. The method of item 1320 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

1412. The method of item 1320 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

1413. The method of item 1320 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

1414. The method of item 1320 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

1415. The method of item 1320 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

1416. The method of item 1320 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

1417. The method of item 1320 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

1418. The method of item 1320 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1419. The method of item 1320 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1420. The method of item 1320 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1421. The method of item 1320 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

1422. The method of item 1320 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1423. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

1424. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

1425. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

1426. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

1427. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

1428. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

1429. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

1430. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

1431. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

1432. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

1433. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

1434. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

1435. The method of item 1320, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

1436. The method of item 1320, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

1437. The method of item 1320, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

1438. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with treatment or prevention of varicose veins.

1439. The method of item 1438 wherein the agent promotes regeneration.

1440. The method of item 1438 wherein the agent promotes angiogenesis.

1441. The method of item 1438 wherein the agent promotes fibroblastmigration.

1442. The method of item 1438 wherein the agent promotes fibroblastproliferation.

1443. The method of item 1438 wherein the agent promotes deposition ofextracellular matrix (ECM).

1444. The method of item 1438 wherein the agent promotes tissueremodeling.

1445. The method of item 1438 wherein the agent is an arterial vesselwall irritant.

1446. The method of item 1438 wherein the fibrosing agent is orcomprises silk.

1447. The method of item 1438 wherein the fibrosing agent is in the formof tufts.

1448. The method of item 1438 wherein the fibrosing agent is orcomprises mineral particles.

1449. The method of item 1438 wherein the fibrosing agent is orcomprises chitosan.

1450. The method of item 1438 wherein the fibrosing agent is orcomprises polylysine.

1451. The method of item 1438 wherein the fibrosing agent is orcomprises fibronectin.

1452. The method of item 1438 wherein the fibrosing agent is orcomprises bleomycin.

1453. The method of item 1438 wherein the fibrosing agent is orcomprises CTGF.

1454. The method of item 1438 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

1455. The method of item 1438 wherein the fibrosing agent is in the formof a particulate.

1456. The method of item 1438, wherein the composition comprises apolymer.

1457. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

1458. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

1459. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

1460. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

1461. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

1462. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

1463. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

1464. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

1465. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

1466. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

1467. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

1468. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

1469. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

1470. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

1471. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

1472. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

1473. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

1474. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

1475. The method of item 1438, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

1476. The method of item 1438, wherein the composition further comprisesa second pharmaceutically active agent.

1477. The method of item 1438, wherein the composition further comprisesan anti-inflammatory agent.

1478. The method of item 1438, wherein the composition further comprisesan agent that inhibits infection.

1479. The method of item 1438, wherein the composition further comprisesan anthracycline.

1480. The method of item 1438, wherein the composition further comprisesdoxorubicin.

1481. The method of item 1438 wherein the composition further comprisesmitoxantrone.

1482. The method of item 1438 wherein the composition further comprisesa fluoropyrimidine.

1483. The method of item 1438, wherein the composition further comprises5-fluorouracil (5-FU).

1484. The method of item 1438, wherein the composition further comprisesa folic acid antagonist.

1485. The method of item 1438, wherein the composition further comprisesmethotrexate.

1486. The method of item 1438, wherein the composition further comprisesa podophylotoxin.

1487. The method of item 1438, wherein the composition further comprisesetoposide.

1488. The method of item 1438, wherein the composition further comprisescamptothecin.

1489. The method of item 1438, wherein the composition further comprisesa hydroxyurea.

1490. The method of item 1438, wherein the composition further comprisesa platinum complex.

1491. The method of item 1438, wherein the composition further comprisescisplatin.

1492. The method of item 1438 wherein the composition further comprisesan anti-thrombotic agent.

1493. The method of item 1438, wherein the composition further comprisesa visualization agent.

1494. The method of item 1438, wherein the composition further comprisesa visualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

1495. The method of item 1438, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

1496. The method of item 1438, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, anMRI responsive material.

1497. The method of item 1438, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, agadolinium chelate.

1498. The method of item 1438, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron, magnesium, manganese, copper, or chromium.

1499. The method of item 1438, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron oxide compound.

1500. The method of item 1438, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

1501. The method of item 1438 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

1502. The method of item 1438 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

1503. The method of item 1438 wherein the composition further comprisesan inflammatory cytokine.

1504. The method of item 1438 wherein the composition further comprisesan agent that stimulates cell proliferation.

1505. The method of item 1438 wherein the composition further comprisesa polymeric carrier.

1506. The method of item 1438 wherein the composition is in the form ofa gel, paste, or spray.

1507. The method of item 1438 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

1508. The method of item 1438 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

1509. The method of item 1438 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

1510. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

1511. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

1512. The method of item 1438 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

1513. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

1514. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

1515. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

1516. The method of item 1438 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

1517. The method of item 1438 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

1518. The method of item 1438 wherein the agent is delivered from adevice, wherein the device is sterile.

1519. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

1520. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

1521. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

1522. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

1523. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

1524. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

1525. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

1526. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

1527. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

1528. The method of item 1438 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

1529. The method of item 1438 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

1530. The method of item 1438 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

1531. The method of item 1438 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

1532. The method of item 1438 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

1533. The method of item 1438 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

1534. The method of item 1438 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

1535. The method of item 1438 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

1536. The method of item 1438 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1537. The method of item 1438 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1538. The method of item 1438 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1539. The method of item 1438 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

1540. The method of item 1438 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1541. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

1542. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

1543. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

1544. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

1545. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

1546. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

1547. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

1548. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

1549. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

1550. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

1551. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

1552. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

1553. The method of item 1438, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

1554. The method of item 1438, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

1555. The method of item 1438, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

1556. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with treatment for urinary incontinence.

1557. The method of item 1556 wherein the agent promotes regeneration.

1558. The method of item 1556 wherein the agent promotes angiogenesis.

1559. The method of item 1556 wherein the agent promotes fibroblastmigration.

1560. The method of item 1556 wherein the agent promotes fibroblastproliferation.

1561. The method of item 1556 wherein the agent promotes deposition ofextracellular matrix (ECM).

1562. The method of item 1556 wherein the agent promotes tissueremodeling.

1563. The method of item 1556 wherein the agent is an arterial vesselwall irritant.

1564. The method of item 1556 wherein the fibrosing agent is orcomprises silk.

1565. The method of item 1556 wherein the fibrosing agent is in the formof tufts.

1566. The method of item 1556 wherein the fibrosing agent is orcomprises mineral particles.

1567. The method of item 1556 wherein the fibrosing agent is orcomprises chitosan.

1568. The method of item 1556 wherein the fibrosing agent is orcomprises polylysine.

1569. The method of item 1556 wherein the fibrosing agent is orcomprises fibronectin.

1570. The method of item 1556 wherein the fibrosing agent is orcomprises bleomycin.

1571. The method of item 1556 wherein the fibrosing agent is orcomprises CTGF.

1572. The method of item 1556 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

1573. The method of item 1556 wherein the fibrosing agent is in the formof a particulate.

1574. The method of item 1556, wherein the composition comprises apolymer.

1575. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

1576. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

1577. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

1578. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

1579. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

1580. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

1581. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

1582. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

1583. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

1584. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

1585. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

1586. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

1587. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

1588. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

1589. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

1590. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

1591. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

1592. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

1593. The method of item 1556, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

1594. The method of item 1556, wherein the composition further comprisesa second pharmaceutically active agent.

1595. The method of item 1556, wherein the composition further comprisesan anti-inflammatory agent.

1596. The method of item 1556, wherein the composition further comprisesan agent that inhibits infection.

1597. The method of item 1556, wherein the composition further comprisesan anthracycline.

1598. The method of item 1556, wherein the composition further comprisesdoxorubicin.

1599. The method of item 1556 wherein the composition further comprisesmitoxantrone.

1600. The method of item 1556 wherein the composition further comprisesa fluoropyrimidine.

1601. The method of item 1556, wherein the composition further comprises5-fluorouracil (5-FU).

1602. The method of item 1556, wherein the composition further comprisesa folic acid antagonist.

1603. The method of item 1556, wherein the composition further comprisesmethotrexate.

1604. The method of item 1556, wherein the composition further comprisesa podophylotoxin.

1605. The method of item 1556, wherein the composition further comprisesetoposide.

1606. The method of item 1556, wherein the composition further comprisescamptothecin.

1607. The method of item 1556, wherein the composition further comprisesa hydroxyurea.

1608. The method of item 1556, wherein the composition further comprisesa platinum complex.

1609. The method of item 1556, wherein the composition further comprisescisplatin.

1610. The method of item 1556 wherein the composition further comprisesan anti-thrombotic agent.

1611. The method of item 1556, wherein the composition further comprisesa visualization agent.

1612. The method of item 1556, wherein the composition further comprisesa visualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

1613. The method of item 1556, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

1614. The method of item 1556, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, anMRI responsive material.

1615. The method of item 1556, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, agadolinium chelate.

1616. The method of item 1556, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron, magnesium, manganese, copper, or chromium.

1617. The method of item 1556, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron oxide compound.

1618. The method of item 1556, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

1619. The method of item 1556 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

1620. The method of item 1556 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

1621. The method of item 1556 wherein the composition further comprisesan inflammatory cytokine.

1622. The method of item 1556 wherein the composition further comprisesan agent that stimulates cell proliferation.

1623. The method of item 1556 wherein the composition further comprisesa polymeric carrier.

1624. The method of item 1556 wherein the composition is in the form ofa gel, paste, or spray.

1625. The method of item 1556 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

1626. The method of item 1556 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

1627. The method of item 1556 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

1628. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

1629. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

1630. The method of item 1556 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

1631. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

1632. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

1633. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

1634. The method of item 1556 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

1635. The method of item 1556 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

1636. The method of item 1556 wherein the agent is delivered from adevice, wherein the device is sterile.

1637. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

1638. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

1639. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

1640. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

1641. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

1642. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

1643. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

1644. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

1645. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

1646. The method of item 1556 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

1647. The method of item 1556 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

1648. The method of item 1556 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

1649. The method of item 1556 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

1650. The method of item 1556 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

1651. The method of item 1556 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

1652. The method of item 1556 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

1653. The method of item 1556 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

1654. The method of item 1556 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1655. The method of item 1556 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1656. The method of item 1556 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1657. The method of item 1556 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

1658. The method of item 1556 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1659. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

1660. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

1661. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

1662. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

1663. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

1664. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

1665. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

1666. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

1667. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

1668. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

1669. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

1670. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

1671. The method of item 1556, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

1672. The method of item 1556, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

1673. The method of item 1556, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

1674. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with contraception.

1675. The method of item 1674 wherein the agent promotes regeneration.

1676. The method of item 1674 wherein the agent promotes angiogenesis.

1677. The method of item 1674 wherein the agent promotes fibroblastmigration.

1678. The method of item 1674 wherein the agent promotes fibroblastproliferation.

1679. The method of item 1674 wherein the agent promotes deposition ofextracellular matrix (ECM).

1680. The method of item 1674 wherein the agent promotes tissueremodeling.

1681. The method of item 1674 wherein the agent is an arterial vesselwall irritant.

1682. The method of item 1674 wherein the fibrosing agent is orcomprises silk.

1683. The method of item 1674 wherein the fibrosing agent is in the formof tufts.

1684. The method of item 1674 wherein the fibrosing agent is orcomprises mineral particles.

1685. The method of item 1674 wherein the fibrosing agent is orcomprises chitosan.

1686. The method of item 1674 wherein the fibrosing agent is orcomprises polylysine.

1687. The method of item 1674 wherein the fibrosing agent is orcomprises fibronectin.

1688. The method of item 1674 wherein the fibrosing agent is orcomprises bleomycin.

1689. The method of item 1674 wherein the fibrosing agent is orcomprises CTGF.

1690. The method of item 1674 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

1691. The method of item 1674 wherein the fibrosing agent is in the formof a particulate.

1692. The method of item 1674, wherein the composition comprises apolymer.

1693. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

1694. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

1695. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

1696. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

1697. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

1698. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

1699. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

1700. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

1701. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

1702. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

1703. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

1704. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

1705. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

1706. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

1707. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

1708. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

1709. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

1710. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

1711. The method of item 1674, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

1712. The method of item 1674, wherein the composition further comprisesa second pharmaceutically active agent.

1713. The method of item 1674, wherein the composition further comprisesan anti-inflammatory agent.

1714. The method of item 1674, wherein the composition further comprisesan agent that inhibits infection.

1715. The method of item 1674, wherein the composition further comprisesan anthracycline.

1716. The method of item 1674, wherein the composition further comprisesdoxorubicin.

1717. The method of item 1674 wherein the composition further comprisesmitoxantrone.

1718. The method of item 1674 wherein the composition further comprisesa fluoropyrimidine.

1719. The method of item 1674, wherein the composition further comprises5-fluorouracil (5-FU).

1720. The method of item 1674, wherein the composition further comprisesa folic acid antagonist.

1721. The method of item 1674, wherein the composition further comprisesmethotrexate.

1722. The method of item 1674, wherein the composition further comprisesa podophylotoxin.

1723. The method of item 1674, wherein the composition further comprisesetoposide.

1724. The method of item 1674, wherein the composition further comprisescamptothecin.

1725. The method of item 1674, wherein the composition further comprisesa hydroxyurea.

1726. The method of item 1674, wherein the composition further comprisesa platinum complex.

1727. The method of item 1674, wherein the composition further comprisescisplatin.

1728. The method of item 1674 wherein the composition further comprisesan anti-thrombotic agent.

1729. The method of item 1674, wherein the composition further comprisesa visualization agent.

1730. The method of item 1674, wherein the composition further comprisesa visualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

1731. The method of item 1674, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

1732. The method of item 1674, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, anMRI responsive material.

1733. The method of item 1674, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, agadolinium chelate.

1734. The method of item 1674, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron, magnesium, manganese, copper, or chromium.

1735. The method of item 1674, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron oxide compound.

1736. The method of item 1674, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

1737. The method of item 1674 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

1738. The method of item 1674 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

1739. The method of item 1674 wherein the composition further comprisesan inflammatory cytokine.

1740. The method of item 1674 wherein the composition further comprisesan agent that stimulates cell proliferation.

1741. The method of item 1674 wherein the composition further comprisesa polymeric carrier.

1742. The method of item 1674 wherein the composition is in the form ofa gel, paste, or spray.

1743. The method of item 1674 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

1744. The method of item 1674 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

1745. The method of item 1674 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

1746. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

1747. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

1748. The method of item 1674 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

1749. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

1750. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

1751. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

1752. The method of item 1674 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

1753. The method of item 1674 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

1754. The method of item 1674 wherein the agent is delivered from adevice, wherein the device is sterile.

1755. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

1756. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

1757. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

1758. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

1759. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

1760. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

1761. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

1762. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

1763. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

1764. The method of item 1674 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

1765. The method of item 1674 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

1766. The method of item 1674 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

1767. The method of item 1674 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

1768. The method of item 1674 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

1769. The method of item 1674 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

1770. The method of item 1674 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

1771. The method of item 1674 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

1772. The method of item 1674 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1773. The method of item 1674 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1774. The method of item 1674 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1775. The method of item 1674 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

1776. The method of item 1674 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1777. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

1778. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

1779. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

1780. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

1781. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

1782. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

1783. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

1784. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

1785. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

1786. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

1787. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

1788. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

1789. The method of item 1674, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

1790. The method of item 1674, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

1791. The method of item 1674, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

1792. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with treatment for an orthopedic condition.

1793. The method of item 1792 wherein the agent promotes regeneration.

1794. The method of item 1792 wherein the agent promotes angiogenesis.

1795. The method of item 1792 wherein the agent promotes fibroblastmigration.

1796. The method of item 1792 wherein the agent promotes fibroblastproliferation.

1797. The method of item 1792 wherein the agent promotes deposition ofextracellular matrix (ECM).

1798. The method of item 1792 wherein the agent promotes tissueremodeling.

1799. The method of item 1792 wherein the agent is an arterial vesselwall irritant.

1800. The method of item 1792 wherein the fibrosing agent is orcomprises silk.

1801. The method of item 1792 wherein the fibrosing agent is in the formof tufts.

1802. The method of item 1792 wherein the fibrosing agent is orcomprises mineral particles.

1803. The method of item 1792 wherein the fibrosing agent is orcomprises chitosan.

1804. The method of item 1792 wherein the fibrosing agent is orcomprises polylysine.

1805. The method of item 1792 wherein the fibrosing agent is orcomprises fibronectin.

1806. The method of item 1792 wherein the fibrosing agent is orcomprises bleomycin.

1807. The method of item 1792 wherein the fibrosing agent is orcomprises CTGF.

1808. The method of item 1792 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

1809. The method of item 1792 wherein the fibrosing agent is in the formof a particulate.

1810. The method of item 1792, wherein the composition comprises apolymer.

1811. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

1812. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

1813. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

1814. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

1815. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

1816. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

1817. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

1818. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

1819. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

1820. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

1821. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

1822. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

1823. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

1824. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

1825. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

1826. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

1827. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

1828. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

1829. The method of item 1792, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

1830. The method of item 1792, wherein the composition further comprisesa second pharmaceutically active agent.

1831. The method of item 1792, wherein the composition further comprisesan anti-inflammatory agent.

1832. The method of item 1792, wherein the composition further comprisesan agent that inhibits infection.

1833. The method of item 1792, wherein the composition further comprisesan anthracycline.

1834. The method of item 1792, wherein the composition further comprisesdoxorubicin.

1835. The method of item 1792 wherein the composition further comprisesmitoxantrone.

1836. The method of item 1792 wherein the composition further comprisesa fluoropyrimidine.

1837. The method of item 1792, wherein the composition further comprises5-fluorouracil (5-FU).

1838. The method of item 1792, wherein the composition further comprisesa folic acid antagonist.

1839. The method of item 1792, wherein the composition further comprisesmethotrexate.

1840. The method of item 1792, wherein the composition further comprisesa podophylotoxin.

1841. The method of item 1792, wherein the composition further comprisesetoposide.

1842. The method of item 1792, wherein the composition further comprisescamptothecin.

1843. The method of item 1792, wherein the composition further comprisesa hydroxyurea.

1844. The method of item 1792, wherein the composition further comprisesa platinum complex.

1845. The method of item 1792, wherein the composition further comprisescisplatin.

1846. The method of item 1792 wherein the composition further comprisesan anti-thrombotic agent.

1847. The method of item 1792, wherein the composition further comprisesa visualization agent.

1848. The method of item 1792, wherein the composition further comprisesa visualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

1849. The method of item 1792, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

1850. The method of item 1792, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, anMRI responsive material.

1851. The method of item 1792, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, agadolinium chelate.

1852. The method of item 1792, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron, magnesium, manganese, copper, or chromium.

1853. The method of item 1792, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron oxide compound.

1854. The method of item 1792, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

1855. The method of item 1792 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

1856. The method of item 1792 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

1857. The method of item 1792 wherein the composition further comprisesan inflammatory cytokine.

1858. The method of item 1792 wherein the composition further comprisesan agent that stimulates cell proliferation.

1859. The method of item 1792 wherein the composition further comprisesa polymeric carrier.

1860. The method of item 1792 wherein the composition is in the form ofa gel, paste, or spray.

1861. The method of item 1792 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

1862. The method of item 1792 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

1863. The method of item 1792 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

1864. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

1865. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

1866. The method of item 1792 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

1867. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

1868. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

1869. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

1870. The method of item 1792 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

1871. The method of item 1792 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

1872. The method of item 1792 wherein the agent is delivered from adevice, wherein the device is sterile.

1873. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

1874. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

1875. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

1876. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

1877. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

1878. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

1879. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

1880. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

1881. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

1882. The method of item 1792 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

1883. The method of item 1792 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

1884. The method of item 1792 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

1885. The method of item 1792 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

1886. The method of item 1792 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

1887. The method of item 1792 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

1888. The method of item 1792 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

1889. The method of item 1792 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

1890. The method of item 1792 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1891. The method of item 1792 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1892. The method of item 1792 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1893. The method of item 1792 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

1894. The method of item 1792 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

1895. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

1896. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

1897. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

1898. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

1899. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

1900. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

1901. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

1902. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

1903. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

1904. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

1905. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

1906. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

1907. The method of item 1792, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

1908. The method of item 1792, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

1909. The method of item 1792, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

1910. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with treatment for a dental condition.

1911. The method of item 1910 wherein the agent promotes regeneration.

1912. The method of item 1910 wherein the agent promotes angiogenesis.

1913. The method of item 1910 wherein the agent promotes fibroblastmigration.

1914. The method of item 1910 wherein the agent promotes fibroblastproliferation.

1915. The method of item 1910 wherein the agent promotes deposition ofextracellular matrix (ECM).

1916. The method of item 1910 wherein the agent promotes tissueremodeling.

1917. The method of item 1910 wherein the agent is an arterial vesselwall irritant.

1918. The method of item 1910 wherein the fibrosing agent is orcomprises silk.

1919. The method of item 1910 wherein the fibrosing agent is in the formof tufts.

1920. The method of item 1910 wherein the fibrosing agent is orcomprises mineral particles.

1921. The method of item 1910 wherein the fibrosing agent is orcomprises chitosan.

1922. The method of item 1910 wherein the fibrosing agent is orcomprises polylysine.

1923. The method of item 1910 wherein the fibrosing agent is orcomprises fibronectin.

1924. The method of item 1910 wherein the fibrosing agent is orcomprises bleomycin.

1925. The method of item 1910 wherein the fibrosing agent is orcomprises CTGF.

1926. The method of item 1910 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

1927. The method of item 1910 wherein the fibrosing agent is in the formof a particulate.

1928. The method of item 1910, wherein the composition comprises apolymer.

1929. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a copolymer.

1930. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a block copolymer.

1931. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a random copolymer.

1932. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a biodegradable polymer.

1933. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-biodegradable polymer.

1934. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophilic polymer.

1935. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrophobic polymer.

1936. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophilicdomains.

1937. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a polymer having hydrophobicdomains.

1938. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a non-conductive polymer.

1939. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, an elastomer.

1940. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrogel.

1941. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a silicone polymer.

1942. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a hydrocarbon polymer.

1943. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a styrene-derived polymer.

1944. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a butadiene-derived polymer.

1945. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a macromer.

1946. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, a poly(ethylene glycol)polymer.

1947. The method of item 1910, wherein the composition comprises apolymer, and the polymer is, or comprises, an amorphous polymer.

1948. The method of item 1910, wherein the composition further comprisesa second pharmaceutically active agent.

1949. The method of item 1910, wherein the composition further comprisesan anti-inflammatory agent.

1950. The method of item 1910, wherein the composition further comprisesan agent that inhibits infection.

1951. The method of item 1910, wherein the composition further comprisesan anthracycline.

1952. The method of item 1910, wherein the composition further comprisesdoxorubicin.

1953. The method of item 1910 wherein the composition further comprisesmitoxantrone.

1954. The method of item 1910 wherein the composition further comprisesa fluoropyrimidine.

1955. The method of item 1910, wherein the composition further comprises5-fluorouracil (5-FU).

1956. The method of item 1910, wherein the composition further comprisesa folic acid antagonist.

1957. The method of item 1910, wherein the composition further comprisesmethotrexate.

1958. The method of item 1910, wherein the composition further comprisesa podophylotoxin.

1959. The method of item 1910, wherein the composition further comprisesetoposide.

1960. The method of item 1910, wherein the composition further comprisescamptothecin.

1961. The method of item 1910, wherein the composition further comprisesa hydroxyurea.

1962. The method of item 1910, wherein the composition further comprisesa platinum complex.

1963. The method of item 1910, wherein the composition further comprisescisplatin.

1964. The method of item 1910 wherein the composition further comprisesan anti-thrombotic agent.

1965. The method of item 1910, wherein the composition further comprisesa visualization agent.

1966. The method of item 1910, wherein the composition further comprisesa visualization agent, and the visualization agent is a radiopaquematerial, wherein the radiopaque material comprises a metal, ahalogenated compound, or a barium containing compound.

1967. The method of item 1910, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,barium, tantalum, or technetium.

1968. The method of item 1910, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, anMRI responsive material.

1969. The method of item 1910, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, agadolinium chelate.

1970. The method of item 1910, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron, magnesium, manganese, copper, or chromium.

1971. The method of item 1910, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises,iron oxide compound.

1972. The method of item 1910, wherein the composition further comprisesa visualization agent, and the visualization agent is, or comprises, adye, pigment, or colorant.

1973. The method of item 1910 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of administrationto about 90 days.

1974. The method of item 1910 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof administration to about 90 days.

1975. The method of item 1910 wherein the composition further comprisesan inflammatory cytokine.

1976. The method of item 1910 wherein the composition further comprisesan agent that stimulates cell proliferation.

1977. The method of item 1910 wherein the composition further comprisesa polymeric carrier.

1978. The method of item 1910 wherein the composition is in the form ofa gel, paste, or spray.

1979. The method of item 1910 wherein the agent is delivered from adevice, and the device delivers the fibrosing agent locally to tissueproximate to the device.

1980. The method of item 1910 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises the fibrosing agent.

1981. The method of item 1910 wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis disposed on a surface of the device.

1982. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingdirectly contacts the device.

1983. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingindirectly contacts the device.

1984. The method of item 1910 wherein the agent is delivered from adevice, wherein the device further comprises a coating, wherein thecoating partially covers the device.

1985. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcompletely covers the device.

1986. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within pores or holes ofthe device.

1987. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is located within a channel, lumen,or divet of the device.

1988. The method of item 1910 wherein the agent is delivered from adevice, wherein the device further comprising an echogenic material.

1989. The method of item 1910 wherein the agent is delivered from adevice, wherein the device further comprises an echogenic material,wherein the echogenic material is in the form of a coating.

1990. The method of item 1910 wherein the agent is delivered from adevice, wherein the device is sterile.

1991. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device.

1992. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is connective tissue.

1993. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is muscle tissue.

1994. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is nerve tissue.

1995. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is released into tissue in thevicinity of the device after deployment of the device, wherein thetissue is epithelium tissue.

1996. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from the time ofdeployment of the device to about 1 year.

1997. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1 monthto 6 months.

1998. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device over a period ranging from about 1-90days.

1999. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a constant rate.

2000. The method of item 1910 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

2001. The method of item 1910 wherein the agent is delivered from adevice, wherein the fibrosing agent is released in effectiveconcentrations from the device at a decreasing rate.

2002. The method of item 1910 wherein the agent is delivered from adevice, wherein the device comprises about 0.01 μg to about 10 μg of thefibrosing agent.

2003. The method of item 1910 wherein the agent is delivered from adevice, wherein the device comprises about 10 μg to about 10 mg of thefibrosing agent.

2004. The method of item 1910 wherein the agent is delivered from adevice, wherein the device comprises about 10 mg to about 250 mg of thefibrosing agent.

2005. The method of item 1910 wherein the agent is delivered from adevice, wherein the device comprises about 250 mg to about 1000 mg ofthe fibrosing agent.

2006. The method of item 1910 wherein the agent is delivered from adevice, wherein the device comprises about 1000 mg to about 2500 mg ofthe fibrosing agent.

2007. The method of item 1910 wherein the agent is delivered from adevice, wherein a surface of the device comprises less than 0.01 μg ofthe fibrosing agent per mm² of device surface to which the fibrosingagent is applied.

2008. The method of item 1910 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 0.01 μg to about1 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

2009. The method of item 1910 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1 μg to about 10μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

2010. The method of item 1910 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 10 μg to about250 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

2011. The method of item 1910 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 250 μg to about1000 μg of the fibrosing agent of fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2012. The method of item 1910 wherein the agent is delivered from adevice, wherein a surface of the device comprises about 1000 μg to about2500 μg of the fibrosing agent per mm² of device surface to which thefibrosing agent is applied.

2013. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a uniform coating.

2014. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a non-uniform coating.

2015. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a discontinuous coating.

2016. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis a patterned coating.

2017. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 100 μm or less.

2018. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatinghas a thickness of 10 μm or less.

2019. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingadheres to the surface of the device upon deployment of the device.

2020. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingis stable at room temperature for a period of at least 1 year.

2021. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

2022. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

2023. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

2024. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

2025. The method of item 1910, wherein the agent is delivered from adevice, wherein the device further comprises a coating, and the coatingcomprises a polymer.

2026. The method of item 1910, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition.

2027. The method of item 1910, wherein the agent is delivered from adevice, wherein the device comprises a first coating having a firstcomposition and a second coating having a second composition, whereinthe first composition and the second composition are different.

2028. A medical device comprising an orthopedic implant and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

2029. The device of item 2028 wherein the fibrosing agent promotesregeneration.

2030. The device of item 2028 wherein the fibrosing agent promotesangiogenesis.

2031. The device of item 2028 wherein the fibrosing agent promotesfibroblast migration.

2032. The device of item 2028 wherein the fibrosing agent promotesfibroblast proliferation.

2033. The device of item 2028 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

2034. The device of item 2028 wherein the fibrosing agent promotestissue remodeling.

2035. The device of item 2028 wherein the fibrosing agent is an arterialvessel wall irritant.

2036. The device of item 2028 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2037. The device of item 2028 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2038. The device of item 2028 wherein the fibrosing agent is orcomprises silk.

2039. The device of item 2028 wherein the fibrosing agent is orcomprises mineral particles.

2040. The device of item 2028 wherein the fibrosing agent is orcomprises chitosan.

2041. The device of item 2028 wherein the fibrosing agent is orcomprises polylysine.

2042. The device of item 2028 wherein the fibrosing agent is orcomprises fibronectin.

2043. The device of item 2028 wherein the fibrosing agent is orcomprises bleomycin.

2044. The device of item 2028 wherein the fibrosing agent is orcomprises CTGF.

2045. The device of item 2028 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

2046. The device of item 2028 wherein the fibrosing agent is in the formof a particulate.

2047. The device of item 2028 wherein the composition further comprisesan inflammatory cytokine.

2048. The device of item 2028 wherein the composition further comprisesan agent that stimulates cell proliferation.

2049. The device of item 2028 wherein the composition is in the form ofa gel, paste, or spray.

2050. The device of item 2028 wherein the fibrosing agent is in the formof tufts.

2051. The device of item 2028, further comprising a polymer.

2052. The device of item 2028, further comprising a polymeric carrier.

2053. The device of item 2028 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2054. The device of item 2028 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2055. The device of item 2028, further comprising a coating, wherein thecoating comprises the fibrosing agent.

2056. The device of item 2028, further comprising a coating, wherein thecoating is disposed on a surface of the device.

2057. The device of item 2028, further comprising a coating, wherein thecoating directly contacts the device.

2058. The device of item 2028, further comprising a coating, wherein thecoating indirectly contacts the device.

2059. The device of item 2028, further comprising a coating, wherein thecoating partially covers the device.

2060. The device of item 2028, further comprising a coating, wherein thecoating completely covers the device.

2061. The device of item 2028, further comprising a coating, wherein thecoating is a uniform coating.

2062. The device of item 2028, further comprising a coating, wherein thecoating is a non-uniform coating.

2063. The device of item 2028, further comprising a coating, wherein thecoating is a discontinuous coating.

2064. The device of item 2028, further comprising a coating, wherein thecoating is a patterned coating.

2065. The device of item 2028, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

2066. The device of item 2028, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

2067. The device of item 2028, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

2068. The device of item 2028, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

2069. The device of item 2028, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

2070. The device of item 2028, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

2071. The device of item 2028, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

2072. The device of item 2028, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

2073. The device of item 2028, further comprising a coating, wherein thecoating further comprises a polymer.

2074. The device of item 2028, further comprising a first coating havinga first composition and the second coating having a second composition.

2075. The device of item 2028, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

2076. The device of item 2028, further comprising a polymer.

2077. The device of item 2028, further comprising a polymeric carrier.

2078. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

2079. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

2080. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

2081. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

2082. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

2083. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

2084. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

2085. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

2086. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

2087. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

2088. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

2089. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

2090. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

2091. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

2092. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

2093. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

2094. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

2095. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

2096. The device of item 2028, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

2097. The device of item 2028, further comprising a lubricious coating.

2098. The device of item 2028 wherein the fibrosing agent is locatedwithin pores or holes of the device.

2099. The device of item 2028 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

2100. The device of item 2028, further comprising a secondpharmaceutically active agent.

2101. The device of item 2028, further comprising an anti-inflammatoryagent.

2102. The device of item 2028, further comprising an agent that inhibitsinfection.

2103. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

2104. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

2105. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

2106. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

2107. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

2108. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

2109. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

2110. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

2111. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

2112. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

2113. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

2114. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

2115. The device of item 2028, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

2116. The device of item 2028, further comprising an anti-thromboticagent.

2117. The device of item 2028, further comprising a visualization agent.

2118. The device of item 2028, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

2119. The device of item 2028, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

2120. The device of item 2028, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

2121. The device of item 2028, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

2122. The device of item 2028, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

2123. The device of item 2028, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

2124. The device of item 2028, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

2125. The device of item 2028, further comprising an echogenic material.

2126. The device of item 2028, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

2127. The device of item 2028 wherein the device is sterile.

2128. The device of item 2028 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

2129. The device of item 2028 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

2130. The device of item 2028 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

2131. The device of item 2028 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

2132. The device of item 2028 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

2133. The device of item 2028 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

2134. The device of item 2028 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

2135. The device of item 2028 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

2136. The device of item 2028 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

2137. The device of item 2028 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

2138. The device of item 2028 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

2139. The device of item 2028 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

2140. The device of item 2028 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

2141. The device of item 2028 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

2142. The device of item 2028 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

2143. The device of item 2028 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

2144. The device of item 2028 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

2145. The device of item 2028 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

2146. The device of item 2028 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

2147. The device of item 2028 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2148. The device of item 2028 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2149. The device of item 2028 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2150. The device of item 2028 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

2151. The device of item 2028 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2152. The device of item 2028 wherein the orthopedic implant is used asa substitute for a bone graft.

2153. The device of item 2028 wherein the orthopedic implant is anorthopedic pin implant.

2154. The device of item 2028 wherein the orthopedic implant is anorthopedic nail implant.

2155. A medical device comprising an orthopedic prosthesis and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

2156. The device of item 2155 wherein the fibrosing agent promotesregeneration.

2157. The device of item 2155 wherein the fibrosing agent promotesangiogenesis.

2158. The device of item 2155 wherein the fibrosing agent promotesfibroblast migration.

2159. The device of item 2155 wherein the fibrosing agent promotesfibroblast proliferation.

2160. The device of item 2155 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

2161. The device of item 2155 wherein the fibrosing agent promotestissue remodeling.

2162. The device of item 2155 wherein the fibrosing agent is an arterialvessel wall irritant.

2163. The device of item 2155 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2164. The device of item 2155 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2165. The device of item 2155 wherein the fibrosing agent is orcomprises silk.

2166. The device of item 2155 wherein the fibrosing agent is orcomprises mineral particles.

2167. The device of item 2155 wherein the fibrosing agent is orcomprises chitosan.

2168. The device of item 2155 wherein the fibrosing agent is orcomprises polylysine.

2169. The device of item 2155 wherein the fibrosing agent is orcomprises fibronectin.

2170. The device of item 2155 wherein the fibrosing agent is orcomprises bleomycin.

2171. The device of item 2155 wherein the fibrosing agent is orcomprises CTGF.

2172. The device of item 2155 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

2173. The device of item 2155 wherein the fibrosing agent is in the formof a particulate.

2174. The device of item 2155 wherein the composition further comprisesan inflammatory cytokine.

2175. The device of item 2155 wherein the composition further comprisesan agent that stimulates cell proliferation.

2176. The device of item 2155 wherein the composition is in the form ofa gel, paste, or spray.

2177. The device of item 2155 wherein the fibrosing agent is in the formof tufts.

2178. The device of item 2155, further comprising a polymer.

2179. The device of item 2155, further comprising a polymeric carrier.

2180. The device of item 2155 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2181. The device of item 2155 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2182. The device of item 2155, further comprising a coating, wherein thecoating comprises the fibrosing agent.

2183. The device of item 2155, further comprising a coating, wherein thecoating is disposed on a surface of the device.

2184. The device of item 2155, further comprising a coating, wherein thecoating directly contacts the device.

2185. The device of item 2155, further comprising a coating, wherein thecoating indirectly contacts the device.

2186. The device of item 2155, further comprising a coating, wherein thecoating partially covers the device.

2187. The device of item 2155, further comprising a coating, wherein thecoating completely covers the device.

2188. The device of item 2155, further comprising a coating, wherein thecoating is a uniform coating.

2189. The device of item 2155, further comprising a coating, wherein thecoating is a non-uniform coating.

2190. The device of item 2155, further comprising a coating, wherein thecoating is a discontinuous coating.

2191. The device of item 2155, further comprising a coating, wherein thecoating is a patterned coating.

2192. The device of item 2155, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

2193. The device of item 2155, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

2194. The device of item 2155, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

2195. The device of item 2155, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

2196. The device of item 2155, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

2197. The device of item 2155, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

2198. The device of item 2155, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

2199. The device of item 2155, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

2200. The device of item 2155, further comprising a coating, wherein thecoating further comprises a polymer.

2201. The device of item 2155, further comprising a first coating havinga first composition and the second coating having a second composition.

2202. The device of item 2155, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

2203. The device of item 2155, further comprising a polymer.

2204. The device of item 2155, further comprising a polymeric carrier.

2205. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

2206. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

2207. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

2208. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

2209. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

2210. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

2211. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

2212. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

2213. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

2214. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

2215. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

2216. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

2217. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

2218. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

2219. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

2220. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

2221. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

2222. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

2223. The device of item 2155, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

2224. The device of item 2155, further comprising a lubricious coating.

2225. The device of item 2155 wherein the fibrosing agent is locatedwithin pores or holes of the device.

2226. The device of item 2155 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

2227. The device of item 2155, further comprising a secondpharmaceutically active agent.

2228. The device of item 2155, further comprising an anti-inflammatoryagent.

2229. The device of item 2155, further comprising an agent that inhibitsinfection.

2230. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

2231. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

2232. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

2233. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

2234. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

2235. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

2236. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

2237. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

2238. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

2239. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

2240. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

2241. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

2242. The device of item 2155, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

2243. The device of item 2155, further comprising an anti-thromboticagent.

2244. The device of item 2155, further comprising a visualization agent.

2245. The device of item 2155, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

2246. The device of item 2155, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

2247. The device of item 2155, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

2248. The device of item 2155, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

2249. The device of item 2155, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

2250. The device of item 2155, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

2251. The device of item 2155, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

2252. The device of item 2155, further comprising an echogenic material.

2253. The device of item 2155, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

2254. The device of item 2155 wherein the device is sterile.

2255. The device of item 2155 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

2256. The device of item 2155 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

2257. The device of item 2155 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

2258. The device of item 2155 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

2259. The device of item 2155 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

2260. The device of item 2155 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

2261. The device of item 2155 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

2262. The device of item 2155 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

2263. The device of item 2155 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

2264. The device of item 2155 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

2265. The device of item 2155 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

2266. The device of item 2155 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

2267. The device of item 2155 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

2268. The device of item 2155 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

2269. The device of item 2155 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

2270. The device of item 2155 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

2271. The device of item 2155 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

2272. The device of item 2155 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

2273. The device of item 2155 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

2274. The device of item 2155 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2275. The device of item 2155 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2276. The device of item 2155 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2277. The device of item 2155 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

2278. The device of item 2155 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2279. A medical device comprising a modular implant and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

2280. The device of item 2279 wherein the fibrosing agent promotesregeneration.

2281. The device of item 2279 wherein the fibrosing agent promotesangiogenesis.

2282. The device of item 2279 wherein the fibrosing agent promotesfibroblast migration.

2283. The device of item 2279 wherein the fibrosing agent promotesfibroblast proliferation.

2284. The device of item 2279 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

2285. The device of item 2279 wherein the fibrosing agent promotestissue remodeling.

2286. The device of item 2279 wherein the fibrosing agent is an arterialvessel wall irritant.

2287. The device of item 2279 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2288. The device of item 2279 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2289. The device of item 2279 wherein the fibrosing agent is orcomprises silk.

2290. The device of item 2279 wherein the fibrosing agent is orcomprises mineral particles.

2291. The device of item 2279 wherein the fibrosing agent is orcomprises chitosan.

2292. The device of item 2279 wherein the fibrosing agent is orcomprises polylysine.

2293. The device of item 2279 wherein the fibrosing agent is orcomprises fibronectin.

2294. The device of item 2279 wherein the fibrosing agent is orcomprises bleomycin.

2295. The device of item 2279 wherein the fibrosing agent is orcomprises CTGF.

2296. The device of item 2279 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

2297. The device of item 2279 wherein the fibrosing agent is in the formof a particulate.

2298. The device of item 2279 wherein the composition further comprisesan inflammatory cytokine.

2299. The device of item 2279 wherein the composition further comprisesan agent that stimulates cell proliferation.

2300. The device of item 2279 wherein the composition is in the form ofa gel, paste, or spray.

2301. The device of item 2279 wherein the fibrosing agent is in the formof tufts.

2302. The device of item 2279, further comprising a polymer.

2303. The device of item 2279, further comprising a polymeric carrier.

2304. The device of item 2279 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2305. The device of item 2279 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2306. The device of item 2279, further comprising a coating, wherein thecoating comprises the fibrosing agent.

2307. The device of item 2279, further comprising a coating, wherein thecoating is disposed on a surface of the device.

2308. The device of item 2279, further comprising a coating, wherein thecoating directly contacts the device.

2309. The device of item 2279, further comprising a coating, wherein thecoating indirectly contacts the device.

2310. The device of item 2279, further comprising a coating, wherein thecoating partially covers the device.

2311. The device of item 2279, further comprising a coating, wherein thecoating completely covers the device.

2312. The device of item 2279, further comprising a coating, wherein thecoating is a uniform coating.

2313. The device of item 2279, further comprising a coating, wherein thecoating is a non-uniform coating.

2314. The device of item 2279, further comprising a coating, wherein thecoating is a discontinuous coating.

2315. The device of item 2279, further comprising a coating, wherein thecoating is a patterned coating.

2316. The device of item 2279, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

2317. The device of item 2279, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

2318. The device of item 2279, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

2319. The device of item 2279, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

2320. The device of item 2279, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

2321. The device of item 2279, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

2322. The device of item 2279, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

2323. The device of item 2279, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

2324. The device of item 2279, further comprising a coating, wherein thecoating further comprises a polymer.

2325. The device of item 2279, further comprising a first coating havinga first composition and the second coating having a second composition.

2326. The device of item 2279, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

2327. The device of item 2279, further comprising a polymer.

2328. The device of item 2279, further comprising a polymeric carrier.

2329. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

2330. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

2331. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

2332. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

2333. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

2334. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

2335. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

2336. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

2337. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

2338. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

2339. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

2340. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

2341. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

2342. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

2343. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

2344. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

2345. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

2346. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

2347. The device of item 2279, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

2348. The device of item 2279, further comprising a lubricious coating.

2349. The device of item 2279 wherein the fibrosing agent is locatedwithin pores or holes of the device.

2350. The device of item 2279 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

2351. The device of item 2279, further comprising a secondpharmaceutically active agent.

2352. The device of item 2279, further comprising an anti-inflammatoryagent.

2353. The device of item 2279, further comprising an agent that inhibitsinfection.

2354. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

2355. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

2356. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

2357. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

2358. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

2359. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

2360. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

2361. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

2362. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

2363. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

2364. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

2365. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

2366. The device of item 2279, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

2367. The device of item 2279, further comprising an anti-thromboticagent.

2368. The device of item 2279, further comprising a visualization agent.

2369. The device of item 2279, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

2370. The device of item 2279, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

2371. The device of item 2279, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

2372. The device of item 2279, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

2373. The device of item 2279, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

2374. The device of item 2279, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

2375. The device of item 2279, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

2376. The device of item 2279, further comprising an echogenic material.

2377. The device of item 2279, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

2378. The device of item 2279 wherein the device is sterile.

2379. The device of item 2279 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

2380. The device of item 2279 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

2381. The device of item 2279 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

2382. The device of item 2279 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

2383. The device of item 2279 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

2384. The device of item 2279 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

2385. The device of item 2279 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

2386. The device of item 2279 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

2387. The device of item 2279 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

2388. The device of item 2279 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

2389. The device of item 2279 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

2390. The device of item 2279 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

2391. The device of item 2279 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

2392. The device of item 2279 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

2393. The device of item 2279 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

2394. The device of item 2279 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

2395. The device of item 2279 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

2396. The device of item 2279 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

2397. The device of item 2279 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

2398. The device of item 2279 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2399. The device of item 2279 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2400. The device of item 2279 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2401. The device of item 2279 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

2402. The device of item 2279 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2403. A medical device comprising a urinary sling and a fibrosing agent,where the fibrosing agent induces a fibrotic response between the deviceand a patient in which the device is implanted.

2404. The device of item 2403 wherein the fibrosing agent promotesregeneration.

2405. The device of item 2403 wherein the fibrosing agent promotesangiogenesis.

2406. The device of item 2403 wherein the fibrosing agent promotesfibroblast migration.

2407. The device of item 2403 wherein the fibrosing agent promotesfibroblast proliferation.

2408. The device of item 2403 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

2409. The device of item 2403 wherein the fibrosing agent promotestissue remodeling.

2410. The device of item 2403 wherein the fibrosing agent is an arterialvessel wall irritant.

2411. The device of item 2403 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2412. The device of item 2403 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2413. The device of item 2403 wherein the fibrosing agent is orcomprises silk.

2414. The device of item 2403 wherein the fibrosing agent is orcomprises mineral particles.

2415. The device of item 2403 wherein the fibrosing agent is orcomprises chitosan.

2416. The device of item 2403 wherein the fibrosing agent is orcomprises polylysine.

2417. The device of item 2403 wherein the fibrosing agent is orcomprises fibronectin.

2418. The device of item 2403 wherein the fibrosing agent is orcomprises bleomycin.

2419. The device of item 2403 wherein the fibrosing agent is orcomprises CTGF.

2420. The device of item 2403 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

2421. The device of item 2403 wherein the fibrosing agent is in the formof a particulate.

2422. The device of item 2403 wherein the composition further comprisesan inflammatory cytokine.

2423. The device of item 2403 wherein the composition further comprisesan agent that stimulates cell proliferation.

2424. The device of item 2403 wherein the composition is in the form ofa gel, paste, or spray.

2425. The device of item 2403 wherein the fibrosing agent is in the formof tufts.

2426. The device of item 2403, further comprising a polymer.

2427. The device of item 2403, further comprising a polymeric carrier.

2428. The device of item 2403 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2429. The device of item 2403 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2430. The device of item 2403, further comprising a coating, wherein thecoating comprises the fibrosing agent.

2431. The device of item 2403, further comprising a coating, wherein thecoating is disposed on a surface of the device.

2432. The device of item 2403, further comprising a coating, wherein thecoating directly contacts the device.

2433. The device of item 2403, further comprising a coating, wherein thecoating indirectly contacts the device.

2434. The device of item 2403, further comprising a coating, wherein thecoating partially covers the device.

2435. The device of item 2403, further comprising a coating, wherein thecoating completely covers the device.

2436. The device of item 2403, further comprising a coating, wherein thecoating is a uniform coating.

2437. The device of item 2403, further comprising a coating, wherein thecoating is a non-uniform coating.

2438. The device of item 2403, further comprising a coating, wherein thecoating is a discontinuous coating.

2439. The device of item 2403, further comprising a coating, wherein thecoating is a patterned coating.

2440. The device of item 2403, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

2441. The device of item 2403, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

2442. The device of item 2403, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

2443. The device of item 2403, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

2444. The device of item 2403, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

2445. The device of item 2403, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

2446. The device of item 2403, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

2447. The device of item 2403, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

2448. The device of item 2403, further comprising a coating, wherein thecoating further comprises a polymer.

2449. The device of item 2403, further comprising a first coating havinga first composition and the second coating having a second composition.

2450. The device of item 2403, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

2451. The device of item 2403, further comprising a polymer.

2452. The device of item 2403, further comprising a polymeric carrier.

2453. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

2454. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

2455. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

2456. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

2457. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

2458. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

2459. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

2460. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

2461. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

2462. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

2463. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

2464. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

2465. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

2466. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

2467. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

2468. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

2469. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

2470. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

2471. The device of item 2403, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

2472. The device of item 2403, further comprising a lubricious coating.

2473. The device of item 2403 wherein the fibrosing agent is locatedwithin pores or holes of the device.

2474. The device of item 2403 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

2475. The device of item 2403, further comprising a secondpharmaceutically active agent.

2476. The device of item 2403, further comprising an anti-inflammatoryagent.

2477. The device of item 2403, further comprising an agent that inhibitsinfection.

2478. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

2479. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

2480. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

2481. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

2482. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

2483. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

2484. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

2485. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

2486. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

2487. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

2488. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

2489. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

2490. The device of item 2403, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

2491. The device of item 2403, further comprising an anti-thromboticagent.

2492. The device of item 2403, further comprising a visualization agent.

2493. The device of item 2403, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

2494. The device of item 2403, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

2495. The device of item 2403, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

2496. The device of item 2403, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

2497. The device of item 2403, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

2498. The device of item 2403, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

2499. The device of item 2403, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

2500. The device of item 2403, further comprising an echogenic material.

2501. The device of item 2403, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

2502. The device of item 2403 wherein the device is sterile.

2503. The device of item 2403 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

2504. The device of item 2403 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

2505. The device of item 2403 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

2506. The device of item 2403 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

2507. The device of item 2403 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

2508. The device of item 2403 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

2509. The device of item 2403 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

2510. The device of item 2403 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

2511. The device of item 2403 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

2512. The device of item 2403 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

2513. The device of item 2403 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

2514. The device of item 2403 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

2515. The device of item 2403 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

2516. The device of item 2403 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

2517. The device of item 2403 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

2518. The device of item 2403 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

2519. The device of item 2403 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

2520. The device of item 2403 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

2521. The device of item 2403 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

2522. The device of item 2403 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2523. The device of item 2403 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2524. The device of item 2403 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2525. The device of item 2403 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

2526. The device of item 2403 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2527. A medical device comprising a prosthetic joint and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

2528. The device of item 2527 wherein the fibrosing agent promotesregeneration.

2529. The device of item 2527 wherein the fibrosing agent promotesangiogenesis.

2530. The device of item 2527 wherein the fibrosing agent promotesfibroblast migration.

2531. The device of item 2527 wherein the fibrosing agent promotesfibroblast proliferation.

2532. The device of item 2527 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

2533. The device of item 2527 wherein the fibrosing agent promotestissue remodeling.

2534. The device of item 2527 wherein the fibrosing agent is an arterialvessel wall irritant.

2535. The device of item 2527 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2536. The device of item 2527 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2537. The device of item 2527 wherein the fibrosing agent is orcomprises silk.

2538. The device of item 2527 wherein the fibrosing agent is orcomprises mineral particles.

2539. The device of item 2527 wherein the fibrosing agent is orcomprises chitosan.

2540. The device of item 2527 wherein the fibrosing agent is orcomprises polylysine.

2541. The device of item 2527 wherein the fibrosing agent is orcomprises fibronectin.

2542. The device of item 2527 wherein the fibrosing agent is orcomprises bleomycin.

2543. The device of item 2527 wherein the fibrosing agent is orcomprises CTGF.

2544. The device of item 2527 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

2545. The device of item 2527 wherein the fibrosing agent is in the formof a particulate.

2546. The device of item 2527 wherein the composition further comprisesan inflammatory cytokine.

2547. The device of item 2527 wherein the composition further comprisesan agent that stimulates cell proliferation.

2548. The device of item 2527 wherein the composition is in the form ofa gel, paste, or spray.

2549. The device of item 2527 wherein the fibrosing agent is in the formof tufts.

2550. The device of item 2527, further comprising a polymer.

2551. The device of item 2527, further comprising a polymeric carrier.

2552. The device of item 2527 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2553. The device of item 2527 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2554. The device of item 2527, further comprising a coating, wherein thecoating comprises the fibrosing agent.

2555. The device of item 2527, further comprising a coating, wherein thecoating is disposed on a surface of the device.

2556. The device of item 2527, further comprising a coating, wherein thecoating directly contacts the device.

2557. The device of item 2527, further comprising a coating, wherein thecoating indirectly contacts the device.

2558. The device of item 2527, further comprising a coating, wherein thecoating partially covers the device.

2559. The device of item 2527, further comprising a coating, wherein thecoating completely covers the device.

2560. The device of item 2527, further comprising a coating, wherein thecoating is a uniform coating.

2561. The device of item 2527, further comprising a coating, wherein thecoating is a non-uniform coating.

2562. The device of item 2527, further comprising a coating, wherein thecoating is a discontinuous coating.

2563. The device of item 2527, further comprising a coating, wherein thecoating is a patterned coating.

2564. The device of item 2527, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

2565. The device of item 2527, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

2566. The device of item 2527, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

2567. The device of item 2527, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

2568. The device of item 2527, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

2569. The device of item 2527, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

2570. The device of item 2527, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

2571. The device of item 2527, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

2572. The device of item 2527, further comprising a coating, wherein thecoating further comprises a polymer.

2573. The device of item 2527, further comprising a first coating havinga first composition and the second coating having a second composition.

2574. The device of item 2527, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

2575. The device of item 2527, further comprising a polymer.

2576. The device of item 2527, further comprising a polymeric carrier.

2577. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

2578. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

2579. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

2580. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

2581. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

2582. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

2583. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

2584. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

2585. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

2586. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

2587. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

2588. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

2589. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

2590. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

2591. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

2592. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

2593. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

2594. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

2595. The device of item 2527, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

2596. The device of item 2527, further comprising a lubricious coating.

2597. The device of item 2527 wherein the fibrosing agent is locatedwithin pores or holes of the device.

2598. The device of item 2527 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

2599. The device of item 2527, further comprising a secondpharmaceutically active agent.

2600. The device of item 2527, further comprising an anti-inflammatoryagent.

2601. The device of item 2527, further comprising an agent that inhibitsinfection.

2602. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

2603. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

2604. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

2605. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

2606. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

2607. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

2608. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

2609. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

2610. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

2611. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

2612. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

2613. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

2614. The device of item 2527, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

2615. The device of item 2527, further comprising an anti-thromboticagent.

2616. The device of item 2527, further comprising a visualization agent.

2617. The device of item 2527, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

2618. The device of item 2527, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

2619. The device of item 2527, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

2620. The device of item 2527, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

2621. The device of item 2527, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

2622. The device of item 2527, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

2623. The device of item 2527, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

2624. The device of item 2527, further comprising an echogenic material.

2625. The device of item 2527, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

2626. The device of item 2527 wherein the device is sterile.

2627. The device of item 2527 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

2628. The device of item 2527 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

2629. The device of item 2527 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

2630. The device of item 2527 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

2631. The device of item 2527 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

2632. The device of item 2527 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

2633. The device of item 2527 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

2634. The device of item 2527 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

2635. The device of item 2527 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

2636. The device of item 2527 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

2637. The device of item 2527 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

2638. The device of item 2527 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

2639. The device of item 2527 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

2640. The device of item 2527 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

2641. The device of item 2527 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

2642. The device of item 2527 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

2643. The device of item 2527 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

2644. The device of item 2527 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

2645. The device of item 2527 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

2646. The device of item 2527 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2647. The device of item 2527 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2648. The device of item 2527 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2649. The device of item 2527 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

2650. The device of item 2527 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2651. A medical device comprising a modular prosthesis and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

2652. The device of item 2651 wherein the fibrosing agent promotesregeneration.

2653. The device of item 2651 wherein the fibrosing agent promotesangiogenesis.

2654. The device of item 2651 wherein the fibrosing agent promotesfibroblast migration.

2655. The device of item 2651 wherein the fibrosing agent promotesfibroblast proliferation.

2656. The device of item 2651 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

2657. The device of item 2651 wherein the fibrosing agent promotestissue remodeling.

2658. The device of item 2651 wherein the fibrosing agent is an arterialvessel wall irritant.

2659. The device of item 2651 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2660. The device of item 2651 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2661. The device of item 2651 wherein the fibrosing agent is orcomprises silk.

2662. The device of item 2651 wherein the fibrosing agent is orcomprises mineral particles.

2663. The device of item 2651 wherein the fibrosing agent is orcomprises chitosan.

2664. The device of item 2651 wherein the fibrosing agent is orcomprises polylysine.

2665. The device of item 2651 wherein the fibrosing agent is orcomprises fibronectin.

2666. The device of item 2651 wherein the fibrosing agent is orcomprises bleomycin.

2667. The device of item 2651 wherein the fibrosing agent is orcomprises CTGF.

2668. The device of item 2651 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

2669. The device of item 2651 wherein the fibrosing agent is in the formof a particulate.

2670. The device of item 2651 wherein the composition further comprisesan inflammatory cytokine.

2671. The device of item 2651 wherein the composition further comprisesan agent that stimulates cell proliferation.

2672. The device of item 2651 wherein the composition is in the form ofa gel, paste, or spray.

2673. The device of item 2651 wherein the fibrosing agent is in the formof tufts.

2674. The device of item 2651, further comprising a polymer.

2675. The device of item 2651, further comprising a polymeric carrier.

2676. The device of item 2651 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2677. The device of item 2651 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2678. The device of item 2651, further comprising a coating, wherein thecoating comprises the fibrosing agent.

2679. The device of item 2651, further comprising a coating, wherein thecoating is disposed on a surface of the device.

2680. The device of item 2651, further comprising a coating, wherein thecoating directly contacts the device.

2681. The device of item 2651, further comprising a coating, wherein thecoating indirectly contacts the device.

2682. The device of item 2651, further comprising a coating, wherein thecoating partially covers the device.

2683. The device of item 2651, further comprising a coating, wherein thecoating completely covers the device.

2684. The device of item 2651, further comprising a coating, wherein thecoating is a uniform coating.

2685. The device of item 2651, further comprising a coating, wherein thecoating is a non-uniform coating.

2686. The device of item 2651, further comprising a coating, wherein thecoating is a discontinuous coating.

2687. The device of item 2651, further comprising a coating, wherein thecoating is a patterned coating.

2688. The device of item 2651, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

2689. The device of item 2651, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

2690. The device of item 2651, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

2691. The device of item 2651, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

2692. The device of item 2651, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

2693. The device of item 2651, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

2694. The device of item 2651, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

2695. The device of item 2651, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

2696. The device of item 2651, further comprising a coating, wherein thecoating further comprises a polymer.

2697. The device of item 2651, further comprising a first coating havinga first composition and the second coating having a second composition.

2698. The device of item 2651, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

2699. The device of item 2651, further comprising a polymer.

2700. The device of item 2651, further comprising a polymeric carrier.

2701. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

2702. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

2703. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

2704. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

2705. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

2706. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

2707. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

2708. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

2709. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

2710. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

2711. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

2712. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

2713. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

2714. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

2715. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

2716. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

2717. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

2718. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

2719. The device of item 2651, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

2720. The device of item 2651, further comprising a lubricious coating.

2721. The device of item 2651 wherein the fibrosing agent is locatedwithin pores or holes of the device.

2722. The device of item 2651 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

2723. The device of item 2651, further comprising a secondpharmaceutically active agent.

2724. The device of item 2651, further comprising an anti-inflammatoryagent.

2725. The device of item 2651, further comprising an agent that inhibitsinfection.

2726. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

2727. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

2728. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

2729. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

2730. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

2731. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

2732. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

2733. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

2734. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

2735. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

2736. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

2737. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

2738. The device of item 2651, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

2739. The device of item 2651, further comprising an anti-thromboticagent.

2740. The device of item 2651, further comprising a visualization agent.

2741. The device of item 2651, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

2742. The device of item 2651, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

2743. The device of item 2651, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

2744. The device of item 2651, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

2745. The device of item 2651, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

2746. The device of item 2651, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

2747. The device of item 2651, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

2748. The device of item 2651, further comprising an echogenic material.

2749. The device of item 2651, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

2750. The device of item 2651 wherein the device is sterile.

2751. The device of item 2651 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

2752. The device of item 2651 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

2753. The device of item 2651 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

2754. The device of item 2651 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

2755. The device of item 2651 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

2756. The device of item 2651 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

2757. The device of item 2651 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

2758. The device of item 2651 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

2759. The device of item 2651 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

2760. The device of item 2651 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

2761. The device of item 2651 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

2762. The device of item 2651 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

2763. The device of item 2651 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

2764. The device of item 2651 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

2765. The device of item 2651 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

2766. The device of item 2651 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

2767. The device of item 2651 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

2768. The device of item 2651 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

2769. The device of item 2651 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

2770. The device of item 2651 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2771. The device of item 2651 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2772. The device of item 2651 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2773. The device of item 2651 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

2774. The device of item 2651 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2775. A medical device comprising a joint prosthesis and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

2776. The device of item 2775 wherein the fibrosing agent promotesregeneration.

2777. The device of item 2775 wherein the fibrosing agent promotesangiogenesis.

2778. The device of item 2775 wherein the fibrosing agent promotesfibroblast migration.

2779. The device of item 2775 wherein the fibrosing agent promotesfibroblast proliferation.

2780. The device of item 2775 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

2781. The device of item 2775 wherein the fibrosing agent promotestissue remodeling.

2782. The device of item 2775 wherein the fibrosing agent is an arterialvessel wall irritant.

2783. The device of item 2775 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2784. The device of item 2775 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2785. The device of item 2775 wherein the fibrosing agent is orcomprises silk.

2786. The device of item 2775 wherein the fibrosing agent is orcomprises mineral particles.

2787. The device of item 2775 wherein the fibrosing agent is orcomprises chitosan.

2788. The device of item 2775 wherein the fibrosing agent is orcomprises polylysine.

2789. The device of item 2775 wherein the fibrosing agent is orcomprises fibronectin.

2790. The device of item 2775 wherein the fibrosing agent is orcomprises bleomycin.

2791. The device of item 2775 wherein the fibrosing agent is orcomprises CTGF.

2792. The device of item 2775 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

2793. The device of item 2775 wherein the fibrosing agent is in the formof a particulate.

2794. The device of item 2775 wherein the composition further comprisesan inflammatory cytokine.

2795. The device of item 2775 wherein the composition further comprisesan agent that stimulates cell proliferation.

2796. The device of item 2775 wherein the composition is in the form ofa gel, paste, or spray.

2797. The device of item 2775 wherein the fibrosing agent is in the formof tufts.

2798. The device of item 2775, further comprising a polymer.

2799. The device of item 2775, further comprising a polymeric carrier.

2800. The device of item 2775 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2801. The device of item 2775 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2802. The device of item 2775, further comprising a coating, wherein thecoating comprises the fibrosing agent.

2803. The device of item 2775, further comprising a coating, wherein thecoating is disposed on a surface of the device.

2804. The device of item 2775, further comprising a coating, wherein thecoating directly contacts the device.

2805. The device of item 2775, further comprising a coating, wherein thecoating indirectly contacts the device.

2806. The device of item 2775, further comprising a coating, wherein thecoating partially covers the device.

2807. The device of item 2775, further comprising a coating, wherein thecoating completely covers the device.

2808. The device of item 2775, further comprising a coating, wherein thecoating is a uniform coating.

2809. The device of item 2775, further comprising a coating, wherein thecoating is a non-uniform coating.

2810. The device of item 2775, further comprising a coating, wherein thecoating is a discontinuous coating.

2811. The device of item 2775, further comprising a coating, wherein thecoating is a patterned coating.

2812. The device of item 2775, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

2813. The device of item 2775, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

2814. The device of item 2775, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

2815. The device of item 2775, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

2816. The device of item 2775, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

2817. The device of item 2775, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

2818. The device of item 2775, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

2819. The device of item 2775, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

2820. The device of item 2775, further comprising a coating, wherein thecoating further comprises a polymer.

2821. The device of item 2775, further comprising a first coating havinga first composition and the second coating having a second composition.

2822. The device of item 2775, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

2823. The device of item 2775, further comprising a polymer.

2824. The device of item 2775, further comprising a polymeric carrier.

2825. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

2826. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

2827. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

2828. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

2829. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

2830. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

2831. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

2832. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

2833. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

2834. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

2835. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

2836. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

2837. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

2838. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

2839. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

2840. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

2841. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

2842. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

2843. The device of item 2775, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

2844. The device of item 2775, further comprising a lubricious coating.

2845. The device of item 2775 wherein the fibrosing agent is locatedwithin pores or holes of the device.

2846. The device of item 2775 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

2847. The device of item 2775, further comprising a secondpharmaceutically active agent.

2848. The device of item 2775, further comprising an anti-inflammatoryagent.

2849. The device of item 2775, further comprising an agent that inhibitsinfection.

2850. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

2851. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

2852. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

2853. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

2854. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

2855. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

2856. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

2857. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

2858. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

2859. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

2860. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

2861. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

2862. The device of item 2775, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

2863. The device of item 2775, further comprising an anti-thromboticagent.

2864. The device of item 2775, further comprising a visualization agent.

2865. The device of item 2775, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

2866. The device of item 2775, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

2867. The device of item 2775, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

2868. The device of item 2775, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

2869. The device of item 2775, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

2870. The device of item 2775, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

2871. The device of item 2775, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

2872. The device of item 2775, further comprising an echogenic material.

2873. The device of item 2775, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

2874. The device of item 2775 wherein the device is sterile.

2875. The device of item 2775 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

2876. The device of item 2775 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

2877. The device of item 2775 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

2878. The device of item 2775 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

2879. The device of item 2775 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

2880. The device of item 2775 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

2881. The device of item 2775 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

2882. The device of item 2775 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

2883. The device of item 2775 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

2884. The device of item 2775 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

2885. The device of item 2775 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

2886. The device of item 2775 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

2887. The device of item 2775 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

2888. The device of item 2775 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

2889. The device of item 2775 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

2890. The device of item 2775 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

2891. The device of item 2775 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

2892. The device of item 2775 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

2893. The device of item 2775 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

2894. The device of item 2775 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2895. The device of item 2775 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2896. The device of item 2775 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2897. The device of item 2775 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

2898. The device of item 2775 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

2899. A medical device comprising a partial prosthesis and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

2900. The device of item 2899 wherein the fibrosing agent promotesregeneration.

2901. The device of item 2899 wherein the fibrosing agent promotesangiogenesis.

2902. The device of item 2899 wherein the fibrosing agent promotesfibroblast migration.

2903. The device of item 2899 wherein the fibrosing agent promotesfibroblast proliferation.

2904. The device of item 2899 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

2905. The device of item 2899 wherein the fibrosing agent promotestissue remodeling.

2906. The device of item 2899 wherein the fibrosing agent is an arterialvessel wall irritant.

2907. The device of item 2899 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2908. The device of item 2899 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2909. The device of item 2899 wherein the fibrosing agent is orcomprises silk.

2910. The device of item 2899 wherein the fibrosing agent is orcomprises mineral particles.

2911. The device of item 2899 wherein the fibrosing agent is orcomprises chitosan.

2912. The device of item 2899 wherein the fibrosing agent is orcomprises polylysine.

2913. The device of item 2899 wherein the fibrosing agent is orcomprises fibronectin.

2914. The device of item 2899 wherein the fibrosing agent is orcomprises bleomycin.

2915. The device of item 2899 wherein the fibrosing agent is orcomprises CTGF.

2916. The device of item 2899 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

2917. The device of item 2899 wherein the fibrosing agent is in the formof a particulate.

2918. The device of item 2899 wherein the composition further comprisesan inflammatory cytokine.

2919. The device of item 2899 wherein the composition further comprisesan agent that stimulates cell proliferation.

2920. The device of item 2899 wherein the composition is in the form ofa gel, paste, or spray.

2921. The device of item 2899 wherein the fibrosing agent is in the formof tufts.

2922. The device of item 2899, further comprising a polymer.

2923. The device of item 2899, further comprising a polymeric carrier.

2924. The device of item 2899 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

2925. The device of item 2899 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

2926. The device of item 2899, further comprising a coating, wherein thecoating comprises the fibrosing agent.

2927. The device of item 2899, further comprising a coating, wherein thecoating is disposed on a surface of the device.

2928. The device of item 2899, further comprising a coating, wherein thecoating directly contacts the device.

2929. The device of item 2899, further comprising a coating, wherein thecoating indirectly contacts the device.

2930. The device of item 2899, further comprising a coating, wherein thecoating partially covers the device.

2931. The device of item 2899, further comprising a coating, wherein thecoating completely covers the device.

2932. The device of item 2899, further comprising a coating, wherein thecoating is a uniform coating.

2933. The device of item 2899, further comprising a coating, wherein thecoating is a non-uniform coating.

2934. The device of item 2899, further comprising a coating, wherein thecoating is a discontinuous coating.

2935. The device of item 2899, further comprising a coating, wherein thecoating is a patterned coating.

2936. The device of item 2899, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

2937. The device of item 2899, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

2938. The device of item 2899, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

2939. The device of item 2899, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

2940. The device of item 2899, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

2941. The device of item 2899, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

2942. The device of item 2899, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

2943. The device of item 2899, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

2944. The device of item 2899, further comprising a coating, wherein thecoating further comprises a polymer.

2945. The device of item 2899, further comprising a first coating havinga first composition and the second coating having a second composition.

2946. The device of item 2899, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

2947. The device of item 2899, further comprising a polymer.

2948. The device of item 2899, further comprising a polymeric carrier.

2949. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

2950. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

2951. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

2952. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

2953. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

2954. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

2955. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

2956. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

2957. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

2958. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

2959. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

2960. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

2961. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

2962. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

2963. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

2964. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

2965. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

2966. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

2967. The device of item 2899, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

2968. The device of item 2899, further comprising a lubricious coating.

2969. The device of item 2899 wherein the fibrosing agent is locatedwithin pores or holes of the device.

2970. The device of item 2899 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

2971. The device of item 2899, further comprising a secondpharmaceutically active agent.

2972. The device of item 2899, further comprising an anti-inflammatoryagent.

2973. The device of item 2899, further comprising an agent that inhibitsinfection.

2974. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

2975. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

2976. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

2977. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

2978. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

2979. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

2980. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

2981. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

2982. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

2983. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

2984. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

2985. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

2986. The device of item 2899, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

2987. The device of item 2899, further comprising an anti-thromboticagent.

2988. The device of item 2899, further comprising a visualization agent.

2989. The device of item 2899, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

2990. The device of item 2899, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

2991. The device of item 2899, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

2992. The device of item 2899, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

2993. The device of item 2899, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

2994. The device of item 2899, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

2995. The device of item 2899, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

2996. The device of item 2899, further comprising an echogenic material.

2997. The device of item 2899, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

2998. The device of item 2899 wherein the device is sterile.

2999. The device of item 2899 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

3000. The device of item 2899 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

3001. The device of item 2899 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

3002. The device of item 2899 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

3003. The device of item 2899 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

3004. The device of item 2899 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

3005. The device of item 2899 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

3006. The device of item 2899 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

3007. The device of item 2899 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

3008. The device of item 2899 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

3009. The device of item 2899 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

3010. The device of item 2899 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

3011. The device of item 2899 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

3012. The device of item 2899 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

3013. The device of item 2899 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

3014. The device of item 2899 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

3015. The device of item 2899 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

3016. The device of item 2899 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

3017. The device of item 2899 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

3018. The device of item 2899 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3019. The device of item 2899 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3020. The device of item 2899 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3021. The device of item 2899 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

3022. The device of item 2899 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3023. A medical device comprising a hip implant and a fibrosing agent,where the fibrosing agent induces a fibrotic response between the deviceand a patient in which the device is implanted.

3024. The device of item 3023 wherein the fibrosing agent promotesregeneration.

3025. The device of item 3023 wherein the fibrosing agent promotesangiogenesis.

3026. The device of item 3023 wherein the fibrosing agent promotesfibroblast migration.

3027. The device of item 3023 wherein the fibrosing agent promotesfibroblast proliferation.

3028. The device of item 3023 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

3029. The device of item 3023 wherein the fibrosing agent promotestissue remodeling.

3030. The device of item 3023 wherein the fibrosing agent is an arterialvessel wall irritant.

3031. The device of item 3023 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3032. The device of item 3023 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3033. The device of item 3023 wherein the fibrosing agent is orcomprises silk.

3034. The device of item 3023 wherein the fibrosing agent is orcomprises mineral particles.

3035. The device of item 3023 wherein the fibrosing agent is orcomprises chitosan.

3036. The device of item 3023 wherein the fibrosing agent is orcomprises polylysine.

3037. The device of item 3023 wherein the fibrosing agent is orcomprises fibronectin.

3038. The device of item 3023 wherein the fibrosing agent is orcomprises bleomycin.

3039. The device of item 3023 wherein the fibrosing agent is orcomprises CTGF.

3040. The device of item 3023 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

3041. The device of item 3023 wherein the fibrosing agent is in the formof a particulate.

3042. The device of item 3023 wherein the composition further comprisesan inflammatory cytokine.

3043. The device of item 3023 wherein the composition further comprisesan agent that stimulates cell proliferation.

3044. The device of item 3023 wherein the composition is in the form ofa gel, paste, or spray.

3045. The device of item 3023 wherein the fibrosing agent is in the formof tufts.

3046. The device of item 3023, further comprising a polymer.

3047. The device of item 3023, further comprising a polymeric carrier.

3048. The device of item 3023 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3049. The device of item 3023 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3050. The device of item 3023, further comprising a coating, wherein thecoating comprises the fibrosing agent.

3051. The device of item 3023, further comprising a coating, wherein thecoating is disposed on a surface of the device.

3052. The device of item 3023, further comprising a coating, wherein thecoating directly contacts the device.

3053. The device of item 3023, further comprising a coating, wherein thecoating indirectly contacts the device.

3054. The device of item 3023, further comprising a coating, wherein thecoating partially covers the device.

3055. The device of item 3023, further comprising a coating, wherein thecoating completely covers the device.

3056. The device of item 3023, further comprising a coating, wherein thecoating is a uniform coating.

3057. The device of item 3023, further comprising a coating, wherein thecoating is a non-uniform coating.

3058. The device of item 3023, further comprising a coating, wherein thecoating is a discontinuous coating.

3059. The device of item 3023, further comprising a coating, wherein thecoating is a patterned coating.

3060. The device of item 3023, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

3061. The device of item 3023, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

3062. The device of item 3023, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

3063. The device of item 3023, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

3064. The device of item 3023, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

3065. The device of item 3023, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

3066. The device of item 3023, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

3067. The device of item 3023, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

3068. The device of item 3023, further comprising a coating, wherein thecoating further comprises a polymer.

3069. The device of item 3023, further comprising a first coating havinga first composition and the second coating having a second composition.

3070. The device of item 3023, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

3071. The device of item 3023, further comprising a polymer.

3072. The device of item 3023, further comprising a polymeric carrier.

3073. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

3074. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

3075. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

3076. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

3077. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

3078. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

3079. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

3080. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

3081. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

3082. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

3083. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

3084. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

3085. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

3086. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

3087. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

3088. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

3089. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

3090. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

3091. The device of item 3023, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

3092. The device of item 3023, further comprising a lubricious coating.

3093. The device of item 3023 wherein the fibrosing agent is locatedwithin pores or holes of the device.

3094. The device of item 3023 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

3095. The device of item 3023, further comprising a secondpharmaceutically active agent.

3096. The device of item 3023, further comprising an anti-inflammatoryagent.

3097. The device of item 3023, further comprising an agent that inhibitsinfection.

3098. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

3099. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

3100. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

3101. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

3102. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

3103. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

3104. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

3105. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

3106. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

3107. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

3108. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

3109. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

3110. The device of item 3023, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

3111. The device of item 3023, further comprising an anti-thromboticagent.

3112. The device of item 3023, further comprising a visualization agent.

3113. The device of item 3023, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

3114. The device of item 3023, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

3115. The device of item 3023, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

3116. The device of item 3023, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

3117. The device of item 3023, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

3118. The device of item 3023, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

3119. The device of item 3023, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

3120. The device of item 3023, further comprising an echogenic material.

3121. The device of item 3023, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

3122. The device of item 3023 wherein the device is sterile.

3123. The device of item 3023 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

3124. The device of item 3023 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

3125. The device of item 3023 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

3126. The device of item 3023 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

3127. The device of item 3023 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

3128. The device of item 3023 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

3129. The device of item 3023 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

3130. The device of item 3023 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

3131. The device of item 3023 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

3132. The device of item 3023 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

3133. The device of item 3023 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

3134. The device of item 3023 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

3135. The device of item 3023 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

3136. The device of item 3023 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

3137. The device of item 3023 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

3138. The device of item 3023 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

3139. The device of item 3023 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

3140. The device of item 3023 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

3141. The device of item 3023 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

3142. The device of item 3023 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3143. The device of item 3023 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3144. The device of item 3023 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3145. The device of item 3023 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

3146. The device of item 3023 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3147. The device of item 3023 wherein the hip implant is a full hipreplacement.

3148. The device of item 3023 wherein the hip implant is a partial hipreplacement.

3149. The device of item 3023 wherein the hip implant is modular.

3150. A medical device comprising a knee implant and a fibrosing agent,where the fibrosing agent induces a fibrotic response between the deviceand a patient in which the device is implanted.

3151. The device of item 3150 wherein the fibrosing agent promotesregeneration.

3152. The device of item 3150 wherein the fibrosing agent promotesangiogenesis.

3153. The device of item 3150 wherein the fibrosing agent promotesfibroblast migration.

3154. The device of item 3150 wherein the fibrosing agent promotesfibroblast proliferation.

3155. The device of item 3150 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

3156. The device of item 3150 wherein the fibrosing agent promotestissue remodeling.

3157. The device of item 3150 wherein the fibrosing agent is an arterialvessel wall irritant.

3158. The device of item 3150 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3159. The device of item 3150 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3160. The device of item 3150 wherein the fibrosing agent is orcomprises silk.

3161. The device of item 3150 wherein the fibrosing agent is orcomprises mineral particles.

3162. The device of item 3150 wherein the fibrosing agent is orcomprises chitosan.

3163. The device of item 3150 wherein the fibrosing agent is orcomprises polylysine.

3164. The device of item 3150 wherein the fibrosing agent is orcomprises fibronectin.

3165. The device of item 3150 wherein the fibrosing agent is orcomprises bleomycin.

3166. The device of item 3150 wherein the fibrosing agent is orcomprises CTGF.

3167. The device of item 3150 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

3168. The device of item 3150 wherein the fibrosing agent is in the formof a particulate.

3169. The device of item 3150 wherein the composition further comprisesan inflammatory cytokine.

3170. The device of item 3150 wherein the composition further comprisesan agent that stimulates cell proliferation.

3171. The device of item 3150 wherein the composition is in the form ofa gel, paste, or spray.

3172. The device of item 3150 wherein the fibrosing agent is in the formof tufts.

3173. The device of item 3150, further comprising a polymer.

3174. The device of item 3150, further comprising a polymeric carrier.

3175. The device of item 3150 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3176. The device of item 3150 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3177. The device of item 3150, further comprising a coating, wherein thecoating comprises the fibrosing agent.

3178. The device of item 3150, further comprising a coating, wherein thecoating is disposed on a surface of the device.

3179. The device of item 3150, further comprising a coating, wherein thecoating directly contacts the device.

3180. The device of item 3150, further comprising a coating, wherein thecoating indirectly contacts the device.

3181. The device of item 3150, further comprising a coating, wherein thecoating partially covers the device.

3182. The device of item 3150, further comprising a coating, wherein thecoating completely covers the device.

3183. The device of item 3150, further comprising a coating, wherein thecoating is a uniform coating.

3184. The device of item 3150, further comprising a coating, wherein thecoating is a non-uniform coating.

3185. The device of item 3150, further comprising a coating, wherein thecoating is a discontinuous coating.

3186. The device of item 3150, further comprising a coating, wherein thecoating is a patterned coating.

3187. The device of item 3150, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

3188. The device of item 3150, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

3189. The device of item 3150, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

3190. The device of item 3150, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

3191. The device of item 3150, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

3192. The device of item 3150, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

3193. The device of item 3150, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

3194. The device of item 3150, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

3195. The device of item 3150, further comprising a coating, wherein thecoating further comprises a polymer.

3196. The device of item 3150, further comprising a first coating havinga first composition and the second coating having a second composition.

3197. The device of item 3150, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

3198. The device of item 3150, further comprising a polymer.

3199. The device of item 3150, further comprising a polymeric carrier.

3200. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

3201. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

3202. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

3203. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

3204. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

3205. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

3206. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

3207. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

3208. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

3209. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

3210. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

3211. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

3212. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

3213. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

3214. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

3215. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

3216. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

3217. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

3218. The device of item 3150, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

3219. The device of item 3150, further comprising a lubricious coating.

3220. The device of item 3150 wherein the fibrosing agent is locatedwithin pores or holes of the device.

3221. The device of item 3150 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

3222. The device of item 3150, further comprising a secondpharmaceutically active agent.

3223. The device of item 3150, further comprising an anti-inflammatoryagent.

3224. The device of item 3150, further comprising an agent that inhibitsinfection.

3225. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

3226. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

3227. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

3228. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

3229. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

3230. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

3231. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

3232. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

3233. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

3234. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

3235. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

3236. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

3237. The device of item 3150, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

3238. The device of item 3150, further comprising an anti-thromboticagent.

3239. The device of item 3150, further comprising a visualization agent.

3240. The device of item 3150, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

3241. The device of item 3150, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

3242. The device of item 3150, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

3243. The device of item 3150, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

3244. The device of item 3150, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

3245. The device of item 3150, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

3246. The device of item 3150, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

3247. The device of item 3150, further comprising an echogenic material.

3248. The device of item 3150, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

3249. The device of item 3150 wherein the device is sterile.

3250. The device of item 3150 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

3251. The device of item 3150 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

3252. The device of item 3150 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

3253. The device of item 3150 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

3254. The device of item 3150 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

3255. The device of item 3150 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

3256. The device of item 3150 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

3257. The device of item 3150 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

3258. The device of item 3150 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

3259. The device of item 3150 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

3260. The device of item 3150 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

3261. The device of item 3150 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

3262. The device of item 3150 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

3263. The device of item 3150 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

3264. The device of item 3150 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

3265. The device of item 3150 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

3266. The device of item 3150 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

3267. The device of item 3150 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

3268. The device of item 3150 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

3269. The device of item 3150 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3270. The device of item 3150 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3271. The device of item 3150 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3272. The device of item 3150 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

3273. The device of item 3150 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3274. A medical device comprising a shoulder implant and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

3275. The device of item 3274 wherein the fibrosing agent promotesregeneration.

3276. The device of item 3274 wherein the fibrosing agent promotesangiogenesis.

3277. The device of item 3274 wherein the fibrosing agent promotesfibroblast migration.

3278. The device of item 3274 wherein the fibrosing agent promotesfibroblast proliferation.

3279. The device of item 3274 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

3280. The device of item 3274 wherein the fibrosing agent promotestissue remodeling.

3281. The device of item 3274 wherein the fibrosing agent is an arterialvessel wall irritant.

3282. The device of item 3274 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3283. The device of item 3274 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3284. The device of item 3274 wherein the fibrosing agent is orcomprises silk.

3285. The device of item 3274 wherein the fibrosing agent is orcomprises mineral particles.

3286. The device of item 3274 wherein the fibrosing agent is orcomprises chitosan.

3287. The device of item 3274 wherein the fibrosing agent is orcomprises polylysine.

3288. The device of item 3274 wherein the fibrosing agent is orcomprises fibronectin.

3289. The device of item 3274 wherein the fibrosing agent is orcomprises bleomycin.

3290. The device of item 3274 wherein the fibrosing agent is orcomprises CTGF.

3291. The device of item 3274 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

3292. The device of item 3274 wherein the fibrosing agent is in the formof a particulate.

3293. The device of item 3274 wherein the composition further comprisesan inflammatory cytokine.

3294. The device of item 3274 wherein the composition further comprisesan agent that stimulates cell proliferation.

3295. The device of item 3274 wherein the composition is in the form ofa gel, paste, or spray.

3296. The device of item 3274 wherein the fibrosing agent is in the formof tufts.

3297. The device of item 3274, further comprising a polymer.

3298. The device of item 3274, further comprising a polymeric carrier.

3299. The device of item 3274 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3300. The device of item 3274 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3301. The device of item 3274, further comprising a coating, wherein thecoating comprises the fibrosing agent.

3302. The device of item 3274, further comprising a coating, wherein thecoating is disposed on a surface of the device.

3303. The device of item 3274, further comprising a coating, wherein thecoating directly contacts the device.

3304. The device of item 3274, further comprising a coating, wherein thecoating indirectly contacts the device.

3305. The device of item 3274, further comprising a coating, wherein thecoating partially covers the device.

3306. The device of item 3274, further comprising a coating, wherein thecoating completely covers the device.

3307. The device of item 3274, further comprising a coating, wherein thecoating is a uniform coating.

3308. The device of item 3274, further comprising a coating, wherein thecoating is a non-uniform coating.

3309. The device of item 3274, further comprising a coating, wherein thecoating is a discontinuous coating.

3310. The device of item 3274, further comprising a coating, wherein thecoating is a patterned coating.

3311. The device of item 3274, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

3312. The device of item 3274, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

3313. The device of item 3274, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

3314. The device of item 3274, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

3315. The device of item 3274, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

3316. The device of item 3274, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

3317. The device of item 3274, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

3318. The device of item 3274, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

3319. The device of item 3274, further comprising a coating, wherein thecoating further comprises a polymer.

3320. The device of item 3274, further comprising a first coating havinga first composition and the second coating having a second composition.

3321. The device of item 3274, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

3322. The device of item 3274, further comprising a polymer.

3323. The device of item 3274, further comprising a polymeric carrier.

3324. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

3325. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

3326. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

3327. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

3328. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

3329. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

3330. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

3331. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

3332. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

3333. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

3334. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

3335. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

3336. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

3337. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

3338. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

3339. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

3340. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

3341. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

3342. The device of item 3274, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

3343. The device of item 3274, further comprising a lubricious coating.

3344. The device of item 3274 wherein the fibrosing agent is locatedwithin pores or holes of the device.

3345. The device of item 3274 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

3346. The device of item 3274, further comprising a secondpharmaceutically active agent.

3347. The device of item 3274, further comprising an anti-inflammatoryagent.

3348. The device of item 3274, further comprising an agent that inhibitsinfection.

3349. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

3350. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

3351. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

3352. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

3353. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

3354. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

3355. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

3356. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

3357. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

3358. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

3359. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

3360. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

3361. The device of item 3274, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

3362. The device of item 3274, further comprising an anti-thromboticagent.

3363. The device of item 3274, further comprising a visualization agent.

3364. The device of item 3274, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

3365. The device of item 3274, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

3366. The device of item 3274, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

3367. The device of item 3274, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

3368. The device of item 3274, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

3369. The device of item 3274, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

3370. The device of item 3274, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

3371. The device of item 3274, further comprising an echogenic material.

3372. The device of item 3274, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

3373. The device of item 3274 wherein the device is sterile.

3374. The device of item 3274 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

3375. The device of item 3274 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

3376. The device of item 3274 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

3377. The device of item 3274 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

3378. The device of item 3274 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

3379. The device of item 3274 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

3380. The device of item 3274 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

3381. The device of item 3274 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

3382. The device of item 3274 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

3383. The device of item 3274 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

3384. The device of item 3274 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

3385. The device of item 3274 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

3386. The device of item 3274 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

3387. The device of item 3274 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

3388. The device of item 3274 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

3389. The device of item 3274 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

3390. The device of item 3274 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

3391. The device of item 3274 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

3392. The device of item 3274 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

3393. The device of item 3274 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3394. The device of item 3274 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3395. The device of item 3274 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3396. The device of item 3274 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

3397. The device of item 3274 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3398. The device of item 3274 wherein the shoulder implant is ahemiarthroplasty.

3399. The device of item 3274 wherein the shoulder implant is a totalshoulder replacement.

3400. A medical device comprising a digit implant and a fibrosing agent,where the fibrosing agent induces a fibrotic response between the deviceand a patient in which the device is implanted.

3401. The device of item 3400 wherein the fibrosing agent promotesregeneration.

3402. The device of item 3400 wherein the fibrosing agent promotesangiogenesis.

3403. The device of item 3400 wherein the fibrosing agent promotesfibroblast migration.

3404. The device of item 3400 wherein the fibrosing agent promotesfibroblast proliferation.

3405. The device of item 3400 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

3406. The device of item 3400 wherein the fibrosing agent promotestissue remodeling.

3407. The device of item 3400 wherein the fibrosing agent is an arterialvessel wall irritant.

3408. The device of item 3400 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3409. The device of item 3400 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3410. The device of item 3400 wherein the fibrosing agent is orcomprises silk.

3411. The device of item 3400 wherein the fibrosing agent is orcomprises mineral particles.

3412. The device of item 3400 wherein the fibrosing agent is orcomprises chitosan.

3413. The device of item 3400 wherein the fibrosing agent is orcomprises polylysine.

3414. The device of item 3400 wherein the fibrosing agent is orcomprises fibronectin.

3415. The device of item 3400 wherein the fibrosing agent is orcomprises bleomycin.

3416. The device of item 3400 wherein the fibrosing agent is orcomprises CTGF.

3417. The device of item 3400 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

3418. The device of item 3400 wherein the fibrosing agent is in the formof a particulate.

3419. The device of item 3400 wherein the composition further comprisesan inflammatory cytokine.

3420. The device of item 3400 wherein the composition further comprisesan agent that stimulates cell proliferation.

3421. The device of item 3400 wherein the composition is in the form ofa gel, paste, or spray.

3422. The device of item 3400 wherein the fibrosing agent is in the formof tufts.

3423. The device of item 3400, further comprising a polymer.

3424. The device of item 3400, further comprising a polymeric carrier.

3425. The device of item 3400 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3426. The device of item 3400 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3427. The device of item 3400, further comprising a coating, wherein thecoating comprises the fibrosing agent.

3428. The device of item 3400, further comprising a coating, wherein thecoating is disposed on a surface of the device.

3429. The device of item 3400, further comprising a coating, wherein thecoating directly contacts the device.

3430. The device of item 3400, further comprising a coating, wherein thecoating indirectly contacts the device.

3431. The device of item 3400, further comprising a coating, wherein thecoating partially covers the device.

3432. The device of item 3400, further comprising a coating, wherein thecoating completely covers the device.

3433. The device of item 3400, further comprising a coating, wherein thecoating is a uniform coating.

3434. The device of item 3400, further comprising a coating, wherein thecoating is a non-uniform coating.

3435. The device of item 3400, further comprising a coating, wherein thecoating is a discontinuous coating.

3436. The device of item 3400, further comprising a coating, wherein thecoating is a patterned coating.

3437. The device of item 3400, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

3438. The device of item 3400, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

3439. The device of item 3400, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

3440. The device of item 3400, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

3441. The device of item 3400, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

3442. The device of item 3400, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

3443. The device of item 3400, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

3444. The device of item 3400, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

3445. The device of item 3400, further comprising a coating, wherein thecoating further comprises a polymer.

3446. The device of item 3400, further comprising a first coating havinga first composition and the second coating having a second composition.

3447. The device of item 3400, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

3448. The device of item 3400, further comprising a polymer.

3449. The device of item 3400, further comprising a polymeric carrier.

3450. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

3451. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

3452. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

3453. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

3454. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

3455. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

3456. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

3457. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

3458. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

3459. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

3460. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

3461. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

3462. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

3463. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

3464. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

3465. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

3466. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

3467. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

3468. The device of item 3400, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

3469. The device of item 3400, further comprising a lubricious coating.

3470. The device of item 3400 wherein the fibrosing agent is locatedwithin pores or holes of the device.

3471. The device of item 3400 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

3472. The device of item 3400, further comprising a secondpharmaceutically active agent.

3473. The device of item 3400, further comprising an anti-inflammatoryagent.

3474. The device of item 3400, further comprising an agent that inhibitsinfection.

3475. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

3476. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

3477. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

3478. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

3479. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

3480. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

3481. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

3482. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

3483. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

3484. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

3485. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

3486. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

3487. The device of item 3400, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

3488. The device of item 3400, further comprising an anti-thromboticagent.

3489. The device of item 3400, further comprising a visualization agent.

3490. The device of item 3400, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

3491. The device of item 3400, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

3492. The device of item 3400, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

3493. The device of item 3400, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

3494. The device of item 3400, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

3495. The device of item 3400, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

3496. The device of item 3400, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

3497. The device of item 3400, further comprising an echogenic material.

3498. The device of item 3400, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

3499. The device of item 3400 wherein the device is sterile.

3500. The device of item 3400 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

3501. The device of item 3400 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

3502. The device of item 3400 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

3503. The device of item 3400 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

3504. The device of item 3400 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

3505. The device of item 3400 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

3506. The device of item 3400 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

3507. The device of item 3400 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

3508. The device of item 3400 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

3509. The device of item 3400 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

3510. The device of item 3400 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

3511. The device of item 3400 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

3512. The device of item 3400 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

3513. The device of item 3400 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

3514. The device of item 3400 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

3515. The device of item 3400 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

3516. The device of item 3400 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

3517. The device of item 3400 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

3518. The device of item 3400 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

3519. The device of item 3400 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3520. The device of item 3400 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3521. The device of item 3400 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3522. The device of item 3400 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

3523. The device of item 3400 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3524. A medical device comprising a titanium fixture for replacement ofthe root portion of a missing natural tooth and a fibrosing agent, wherethe fibrosing agent induces a fibrotic response between the device and apatient in which the device is implanted.

3525. The device of item 3524 wherein the fibrosing agent promotesregeneration.

3526. The device of item 3524 wherein the fibrosing agent promotesangiogenesis.

3527. The device of item 3524 wherein the fibrosing agent promotesfibroblast migration.

3528. The device of item 3524 wherein the fibrosing agent promotesfibroblast proliferation.

3529. The device of item 3524 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

3530. The device of item 3524 wherein the fibrosing agent promotestissue remodeling.

3531. The device of item 3524 wherein the fibrosing agent is an arterialvessel wall irritant.

3532. The device of item 3524 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3533. The device of item 3524 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3534. The device of item 3524 wherein the fibrosing agent is orcomprises silk.

3535. The device of item 3524 wherein the fibrosing agent is orcomprises mineral particles.

3536. The device of item 3524 wherein the fibrosing agent is orcomprises chitosan.

3537. The device of item 3524 wherein the fibrosing agent is orcomprises polylysine.

3538. The device of item 3524 wherein the fibrosing agent is orcomprises fibronectin.

3539. The device of item 3524 wherein the fibrosing agent is orcomprises bleomycin.

3540. The device of item 3524 wherein the fibrosing agent is orcomprises CTGF.

3541. The device of item 3524 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

3542. The device of item 3524 wherein the fibrosing agent is in the formof a particulate.

3543. The device of item 3524 wherein the composition further comprisesan inflammatory cytokine.

3544. The device of item 3524 wherein the composition further comprisesan agent that stimulates cell proliferation.

3545. The device of item 3524 wherein the composition is in the form ofa gel, paste, or spray.

3546. The device of item 3524 wherein the fibrosing agent is in the formof tufts.

3547. The device of item 3524, further comprising a polymer.

3548. The device of item 3524, further comprising a polymeric carrier.

3549. The device of item 3524 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3550. The device of item 3524 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3551. The device of item 3524, further comprising a coating, wherein thecoating comprises the fibrosing agent.

3552. The device of item 3524, further comprising a coating, wherein thecoating is disposed on a surface of the device.

3553. The device of item 3524, further comprising a coating, wherein thecoating directly contacts the device.

3554. The device of item 3524, further comprising a coating, wherein thecoating indirectly contacts the device.

3555. The device of item 3524, further comprising a coating, wherein thecoating partially covers the device.

3556. The device of item 3524, further comprising a coating, wherein thecoating completely covers the device.

3557. The device of item 3524, further comprising a coating, wherein thecoating is a uniform coating.

3558. The device of item 3524, further comprising a coating, wherein thecoating is a non-uniform coating.

3559. The device of item 3524, further comprising a coating, wherein thecoating is a discontinuous coating.

3560. The device of item 3524, further comprising a coating, wherein thecoating is a patterned coating.

3561. The device of item 3524, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

3562. The device of item 3524, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

3563. The device of item 3524, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

3564. The device of item 3524, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

3565. The device of item 3524, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

3566. The device of item 3524, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

3567. The device of item 3524, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

3568. The device of item 3524, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

3569. The device of item 3524, further comprising a coating, wherein thecoating further comprises a polymer.

3570. The device of item 3524, further comprising a first coating havinga first composition and the second coating having a second composition.

3571. The device of item 3524, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

3572. The device of item 3524, further comprising a polymer.

3573. The device of item 3524, further comprising a polymeric carrier.

3574. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

3575. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

3576. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

3577. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

3578. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

3579. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

3580. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

3581. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

3582. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

3583. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

3584. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

3585. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

3586. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

3587. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

3588. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

3589. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

3590. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

3591. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

3592. The device of item 3524, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

3593. The device of item 3524, further comprising a lubricious coating.

3594. The device of item 3524 wherein the fibrosing agent is locatedwithin pores or holes of the device.

3595. The device of item 3524 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

3596. The device of item 3524, further comprising a secondpharmaceutically active agent.

3597. The device of item 3524, further comprising an anti-inflammatoryagent.

3598. The device of item 3524, further comprising an agent that inhibitsinfection.

3599. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

3600. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

3601. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

3602. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

3603. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

3604. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

3605. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

3606. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

3607. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

3608. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

3609. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

3610. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

3611. The device of item 3524, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

3612. The device of item 3524, further comprising an anti-thromboticagent.

3613. The device of item 3524, further comprising a visualization agent.

3614. The device of item 3524, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

3615. The device of item 3524, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

3616. The device of item 3524, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

3617. The device of item 3524, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

3618. The device of item 3524, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

3619. The device of item 3524, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

3620. The device of item 3524, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

3621. The device of item 3524, further comprising an echogenic material.

3622. The device of item 3524, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

3623. The device of item 3524 wherein the device is sterile.

3624. The device of item 3524 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

3625. The device of item 3524 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

3626. The device of item 3524 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

3627. The device of item 3524 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

3628. The device of item 3524 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

3629. The device of item 3524 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

3630. The device of item 3524 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

3631. The device of item 3524 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

3632. The device of item 3524 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

3633. The device of item 3524 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

3634. The device of item 3524 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

3635. The device of item 3524 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

3636. The device of item 3524 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

3637. The device of item 3524 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

3638. The device of item 3524 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

3639. The device of item 3524 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

3640. The device of item 3524 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

3641. The device of item 3524 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

3642. The device of item 3524 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

3643. The device of item 3524 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3644. The device of item 3524 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3645. The device of item 3524 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3646. The device of item 3524 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

3647. The device of item 3524 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3648. A medical device comprising an endosteal implant and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

3649. The device of item 3648 wherein the fibrosing agent promotesregeneration.

3650. The device of item 3648 wherein the fibrosing agent promotesangiogenesis.

3651. The device of item 3648 wherein the fibrosing agent promotesfibroblast migration.

3652. The device of item 3648 wherein the fibrosing agent promotesfibroblast proliferation.

3653. The device of item 3648 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

3654. The device of item 3648 wherein the fibrosing agent promotestissue remodeling.

3655. The device of item 3648 wherein the fibrosing agent is an arterialvessel wall irritant.

3656. The device of item 3648 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3657. The device of item 3648 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3658. The device of item 3648 wherein the fibrosing agent is orcomprises silk.

3659. The device of item 3648 wherein the fibrosing agent is orcomprises mineral particles.

3660. The device of item 3648 wherein the fibrosing agent is orcomprises chitosan.

3661. The device of item 3648 wherein the fibrosing agent is orcomprises polylysine.

3662. The device of item 3648 wherein the fibrosing agent is orcomprises fibronectin.

3663. The device of item 3648 wherein the fibrosing agent is orcomprises bleomycin.

3664. The device of item 3648 wherein the fibrosing agent is orcomprises CTGF.

3665. The device of item 3648 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

3666. The device of item 3648 wherein the fibrosing agent is in the formof a particulate.

3667. The device of item 3648 wherein the composition further comprisesan inflammatory cytokine.

3668. The device of item 3648 wherein the composition further comprisesan agent that stimulates cell proliferation.

3669. The device of item 3648 wherein the composition is in the form ofa gel, paste, or spray.

3670. The device of item 3648 wherein the fibrosing agent is in the formof tufts.

3671. The device of item 3648, further comprising a polymer.

3672. The device of item 3648, further comprising a polymeric carrier.

3673. The device of item 3648 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3674. The device of item 3648 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3675. The device of item 3648, further comprising a coating, wherein thecoating comprises the fibrosing agent.

3676. The device of item 3648, further comprising a coating, wherein thecoating is disposed on a surface of the device.

3677. The device of item 3648, further comprising a coating, wherein thecoating directly contacts the device.

3678. The device of item 3648, further comprising a coating, wherein thecoating indirectly contacts the device.

3679. The device of item 3648, further comprising a coating, wherein thecoating partially covers the device.

3680. The device of item 3648, further comprising a coating, wherein thecoating completely covers the device.

3681. The device of item 3648, further comprising a coating, wherein thecoating is a uniform coating.

3682. The device of item 3648, further comprising a coating, wherein thecoating is a non-uniform coating.

3683. The device of item 3648, further comprising a coating, wherein thecoating is a discontinuous coating.

3684. The device of item 3648, further comprising a coating, wherein thecoating is a patterned coating.

3685. The device of item 3648, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

3686. The device of item 3648, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

3687. The device of item 3648, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

3688. The device of item 3648, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

3689. The device of item 3648, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

3690. The device of item 3648, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

3691. The device of item 3648, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

3692. The device of item 3648, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

3693. The device of item 3648, further comprising a coating, wherein thecoating further comprises a polymer.

3694. The device of item 3648, further comprising a first coating havinga first composition and the second coating having a second composition.

3695. The device of item 3648, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

3696. The device of item 3648, further comprising a polymer.

3697. The device of item 3648, further comprising a polymeric carrier.

3698. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

3699. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

3700. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

3701. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

3702. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

3703. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

3704. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

3705. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

3706. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

3707. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

3708. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

3709. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

3710. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

3711. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

3712. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

3713. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

3714. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

3715. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

3716. The device of item 3648, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

3717. The device of item 3648, further comprising a lubricious coating.

3718. The device of item 3648 wherein the fibrosing agent is locatedwithin pores or holes of the device.

3719. The device of item 3648 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

3720. The device of item 3648, further comprising a secondpharmaceutically active agent.

3721. The device of item 3648, further comprising an anti-inflammatoryagent.

3722. The device of item 3648, further comprising an agent that inhibitsinfection.

3723. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

3724. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

3725. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

3726. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

3727. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

3728. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

3729. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

3730. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

3731. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

3732. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

3733. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

3734. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

3735. The device of item 3648, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

3736. The device of item 3648, further comprising an anti-thromboticagent.

3737. The device of item 3648, further comprising a visualization agent.

3738. The device of item 3648, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

3739. The device of item 3648, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

3740. The device of item 3648, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

3741. The device of item 3648, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

3742. The device of item 3648, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

3743. The device of item 3648, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

3744. The device of item 3648, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

3745. The device of item 3648, further comprising an echogenic material.

3746. The device of item 3648, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

3747. The device of item 3648 wherein the device is sterile.

3748. The device of item 3648 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

3749. The device of item 3648 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

3750. The device of item 3648 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

3751. The device of item 3648 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

3752. The device of item 3648 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

3753. The device of item 3648 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

3754. The device of item 3648 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

3755. The device of item 3648 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

3756. The device of item 3648 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

3757. The device of item 3648 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

3758. The device of item 3648 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

3759. The device of item 3648 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

3760. The device of item 3648 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

3761. The device of item 3648 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

3762. The device of item 3648 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

3763. The device of item 3648 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

3764. The device of item 3648 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

3765. The device of item 3648 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

3766. The device of item 3648 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

3767. The device of item 3648 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3768. The device of item 3648 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3769. The device of item 3648 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3770. The device of item 3648 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

3771. The device of item 3648 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3772. A medical device comprising a subperiosteal implant and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

3773. The device of item 3772 wherein the fibrosing agent promotesregeneration.

3774. The device of item 3772 wherein the fibrosing agent promotesangiogenesis.

3775. The device of item 3772 wherein the fibrosing agent promotesfibroblast migration.

3776. The device of item 3772 wherein the fibrosing agent promotesfibroblast proliferation.

3777. The device of item 3772 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

3778. The device of item 3772 wherein the fibrosing agent promotestissue remodeling.

3779. The device of item 3772 wherein the fibrosing agent is an arterialvessel wall irritant.

3780. The device of item 3772 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3781. The device of item 3772 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3782. The device of item 3772 wherein the fibrosing agent is orcomprises silk.

3783. The device of item 3772 wherein the fibrosing agent is orcomprises mineral particles.

3784. The device of item 3772 wherein the fibrosing agent is orcomprises chitosan.

3785. The device of item 3772 wherein the fibrosing agent is orcomprises polylysine.

3786. The device of item 3772 wherein the fibrosing agent is orcomprises fibronectin.

3787. The device of item 3772 wherein the fibrosing agent is orcomprises bleomycin.

3788. The device of item 3772 wherein the fibrosing agent is orcomprises CTGF.

3789. The device of item 3772 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

3790. The device of item 3772 wherein the fibrosing agent is in the formof a particulate.

3791. The device of item 3772 wherein the composition further comprisesan inflammatory cytokine.

3792. The device of item 3772 wherein the composition further comprisesan agent that stimulates cell proliferation.

3793. The device of item 3772 wherein the composition is in the form ofa gel, paste, or spray.

3794. The device of item 3772 wherein the fibrosing agent is in the formof tufts.

3795. The device of item 3772, further comprising a polymer.

3796. The device of item 3772, further comprising a polymeric carrier.

3797. The device of item 3772 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3798. The device of item 3772 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3799. The device of item 3772, further comprising a coating, wherein thecoating comprises the fibrosing agent.

3800. The device of item 3772, further comprising a coating, wherein thecoating is disposed on a surface of the device.

3801. The device of item 3772, further comprising a coating, wherein thecoating directly contacts the device.

3802. The device of item 3772, further comprising a coating, wherein thecoating indirectly contacts the device.

3803. The device of item 3772, further comprising a coating, wherein thecoating partially covers the device.

3804. The device of item 3772, further comprising a coating, wherein thecoating completely covers the device.

3805. The device of item 3772, further comprising a coating, wherein thecoating is a uniform coating.

3806. The device of item 3772, further comprising a coating, wherein thecoating is a non-uniform coating.

3807. The device of item 3772, further comprising a coating, wherein thecoating is a discontinuous coating.

3808. The device of item 3772, further comprising a coating, wherein thecoating is a patterned coating.

3809. The device of item 3772, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

3810. The device of item 3772, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

3811. The device of item 3772, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

3812. The device of item 3772, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

3813. The device of item 3772, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

3814. The device of item 3772, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

3815. The device of item 3772, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

3816. The device of item 3772, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

3817. The device of item 3772, further comprising a coating, wherein thecoating further comprises a polymer.

3818. The device of item 3772, further comprising a first coating havinga first composition and the second coating having a second composition.

3819. The device of item 3772, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

3820. The device of item 3772, further comprising a polymer.

3821. The device of item 3772, further comprising a polymeric carrier.

3822. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

3823. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

3824. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

3825. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

3826. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

3827. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

3828. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

3829. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

3830. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

3831. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

3832. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

3833. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

3834. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

3835. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

3836. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

3837. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

3838. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

3839. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

3840. The device of item 3772, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

3841. The device of item 3772, further comprising a lubricious coating.

3842. The device of item 3772 wherein the fibrosing agent is locatedwithin pores or holes of the device.

3843. The device of item 3772 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

3844. The device of item 3772, further comprising a secondpharmaceutically active agent.

3845. The device of item 3772, further comprising an anti-inflammatoryagent.

3846. The device of item 3772, further comprising an agent that inhibitsinfection.

3847. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

3848. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

3849. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

3850. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

3851. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

3852. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

3853. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

3854. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

3855. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

3856. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

3857. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

3858. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

3859. The device of item 3772, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

3860. The device of item 3772, further comprising an anti-thromboticagent.

3861. The device of item 3772, further comprising a visualization agent.

3862. The device of item 3772, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

3863. The device of item 3772, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

3864. The device of item 3772, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

3865. The device of item 3772, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

3866. The device of item 3772, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

3867. The device of item 3772, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

3868. The device of item 3772, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

3869. The device of item 3772, further comprising an echogenic material.

3870. The device of item 3772, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

3871. The device of item 3772 wherein the device is sterile.

3872. The device of item 3772 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

3873. The device of item 3772 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

3874. The device of item 3772 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

3875. The device of item 3772 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

3876. The device of item 3772 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

3877. The device of item 3772 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

3878. The device of item 3772 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

3879. The device of item 3772 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

3880. The device of item 3772 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

3881. The device of item 3772 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

3882. The device of item 3772 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

3883. The device of item 3772 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

3884. The device of item 3772 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

3885. The device of item 3772 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

3886. The device of item 3772 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

3887. The device of item 3772 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

3888. The device of item 3772 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

3889. The device of item 3772 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

3890. The device of item 3772 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

3891. The device of item 3772 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3892. The device of item 3772 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3893. The device of item 3772 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3894. The device of item 3772 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

3895. The device of item 3772 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

3896. A medical device comprising a guided bone regeneration (GBR)implant and a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

3897. The device of item 3896 wherein the fibrosing agent promotesregeneration.

3898. The device of item 3896 wherein the fibrosing agent promotesangiogenesis.

3899. The device of item 3896 wherein the fibrosing agent promotesfibroblast migration.

3900. The device of item 3896 wherein the fibrosing agent promotesfibroblast proliferation.

3901. The device of item 3896 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

3902. The device of item 3896 wherein the fibrosing agent promotestissue remodeling.

3903. The device of item 3896 wherein the fibrosing agent is an arterialvessel wall irritant.

3904. The device of item 3896 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3905. The device of item 3896 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3906. The device of item 3896 wherein the fibrosing agent is orcomprises silk.

3907. The device of item 3896 wherein the fibrosing agent is orcomprises mineral particles.

3908. The device of item 3896 wherein the fibrosing agent is orcomprises chitosan.

3909. The device of item 3896 wherein the fibrosing agent is orcomprises polylysine.

3910. The device of item 3896 wherein the fibrosing agent is orcomprises fibronectin.

3911. The device of item 3896 wherein the fibrosing agent is orcomprises bleomycin.

3912. The device of item 3896 wherein the fibrosing agent is orcomprises CTGF.

3913. The device of item 3896 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

3914. The device of item 3896 wherein the fibrosing agent is in the formof a particulate.

3915. The device of item 3896 wherein the composition further comprisesan inflammatory cytokine.

3916. The device of item 3896 wherein the composition further comprisesan agent that stimulates cell proliferation.

3917. The device of item 3896 wherein the composition is in the form ofa gel, paste, or spray.

3918. The device of item 3896 wherein the fibrosing agent is in the formof tufts.

3919. The device of item 3896, further comprising a polymer.

3920. The device of item 3896, further comprising a polymeric carrier.

3921. The device of item 3896 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

3922. The device of item 3896 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

3923. The device of item 3896, further comprising a coating, wherein thecoating comprises the fibrosing agent.

3924. The device of item 3896, further comprising a coating, wherein thecoating is disposed on a surface of the device.

3925. The device of item 3896, further comprising a coating, wherein thecoating directly contacts the device.

3926. The device of item 3896, further comprising a coating, wherein thecoating indirectly contacts the device.

3927. The device of item 3896, further comprising a coating, wherein thecoating partially covers the device.

3928. The device of item 3896, further comprising a coating, wherein thecoating completely covers the device.

3929. The device of item 3896, further comprising a coating, wherein thecoating is a uniform coating.

3930. The device of item 3896, further comprising a coating, wherein thecoating is a non-uniform coating.

3931. The device of item 3896, further comprising a coating, wherein thecoating is a discontinuous coating.

3932. The device of item 3896, further comprising a coating, wherein thecoating is a patterned coating.

3933. The device of item 3896, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

3934. The device of item 3896, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

3935. The device of item 3896, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

3936. The device of item 3896, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

3937. The device of item 3896, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

3938. The device of item 3896, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

3939. The device of item 3896, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

3940. The device of item 3896, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

3941. The device of item 3896, further comprising a coating, wherein thecoating further comprises a polymer.

3942. The device of item 3896, further comprising a first coating havinga first composition and the second coating having a second composition.

3943. The device of item 3896, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

3944. The device of item 3896, further comprising a polymer.

3945. The device of item 3896, further comprising a polymeric carrier.

3946. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

3947. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

3948. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

3949. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

3950. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

3951. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

3952. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

3953. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

3954. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

3955. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

3956. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

3957. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

3958. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

3959. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

3960. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

3961. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

3962. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

3963. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

3964. The device of item 3896, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

3965. The device of item 3896, further comprising a lubricious coating.

3966. The device of item 3896 wherein the fibrosing agent is locatedwithin pores or holes of the device.

3967. The device of item 3896 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

3968. The device of item 3896, further comprising a secondpharmaceutically active agent.

3969. The device of item 3896, further comprising an anti-inflammatoryagent.

3970. The device of item 3896, further comprising an agent that inhibitsinfection.

3971. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

3972. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

3973. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

3974. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

3975. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

3976. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

3977. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

3978. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

3979. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

3980. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

3981. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

3982. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

3983. The device of item 3896, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

3984. The device of item 3896, further comprising an anti-thromboticagent.

3985. The device of item 3896, further comprising a visualization agent.

3986. The device of item 3896, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

3987. The device of item 3896, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

3988. The device of item 3896, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

3989. The device of item 3896, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

3990. The device of item 3896, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

3991. The device of item 3896, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

3992. The device of item 3896, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

3993. The device of item 3896, further comprising an echogenic material.

3994. The device of item 3896, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

3995. The device of item 3896 wherein the device is sterile.

3996. The device of item 3896 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

3997. The device of item 3896 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

3998. The device of item 3896 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

3999. The device of item 3896 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

4000. The device of item 3896 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

4001. The device of item 3896 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

4002. The device of item 3896 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

4003. The device of item 3896 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

4004. The device of item 3896 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

4005. The device of item 3896 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

4006. The device of item 3896 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

4007. The device of item 3896 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

4008. The device of item 3896 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

4009. The device of item 3896 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

4010. The device of item 3896 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

4011. The device of item 3896 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

4012. The device of item 3896 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

4013. The device of item 3896 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

4014. The device of item 3896 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

4015. The device of item 3896 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4016. The device of item 3896 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4017. The device of item 3896 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4018. The device of item 3896 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

4019. The device of item 3896 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4020. The medical device of claqim 3896 wherein the GBR is resorbablebone substitutes for filing bony defects.

4021. A medical device comprising a dental implant to control thehealing process subsequent to periodontal disease and a fibrosing agent,where the fibrosing agent induces a fibrotic response between the deviceand a patient in which the device is implanted.

4022. The device of item 4021 wherein the fibrosing agent promotesregeneration.

4023. The device of item 4021 wherein the fibrosing agent promotesangiogenesis.

4024. The device of item 4021 wherein the fibrosing agent promotesfibroblast migration.

4025. The device of item 4021 wherein the fibrosing agent promotesfibroblast proliferation.

4026. The device of item 4021 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

4027. The device of item 4021 wherein the fibrosing agent promotestissue remodeling.

4028. The device of item 4021 wherein the fibrosing agent is an arterialvessel wall irritant.

4029. The device of item 4021 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4030. The device of item 4021 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4031. The device of item 4021 wherein the fibrosing agent is orcomprises silk.

4032. The device of item 4021 wherein the fibrosing agent is orcomprises mineral particles.

4033. The device of item 4021 wherein the fibrosing agent is orcomprises chitosan.

4034. The device of item 4021 wherein the fibrosing agent is orcomprises polylysine.

4035. The device of item 4021 wherein the fibrosing agent is orcomprises fibronectin.

4036. The device of item 4021 wherein the fibrosing agent is orcomprises bleomycin.

4037. The device of item 4021 wherein the fibrosing agent is orcomprises CTGF.

4038. The device of item 4021 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

4039. The device of item 4021 wherein the fibrosing agent is in the formof a particulate.

4040. The device of item 4021 wherein the composition further comprisesan inflammatory cytokine.

4041. The device of item 4021 wherein the composition further comprisesan agent that stimulates cell proliferation.

4042. The device of item 4021 wherein the composition is in the form ofa gel, paste, or spray.

4043. The device of item 4021 wherein the fibrosing agent is in the formof tufts.

4044. The device of item 4021, further comprising a polymer.

4045. The device of item 4021, further comprising a polymeric carrier.

4046. The device of item 4021 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4047. The device of item 4021 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4048. The device of item 4021, further comprising a coating, wherein thecoating comprises the fibrosing agent.

4049. The device of item 4021, further comprising a coating, wherein thecoating is disposed on a surface of the device.

4050. The device of item 4021, further comprising a coating, wherein thecoating directly contacts the device.

4051. The device of item 4021, further comprising a coating, wherein thecoating indirectly contacts the device.

4052. The device of item 4021, further comprising a coating, wherein thecoating partially covers the device.

4053. The device of item 4021, further comprising a coating, wherein thecoating completely covers the device.

4054. The device of item 4021, further comprising a coating, wherein thecoating is a uniform coating.

4055. The device of item 4021, further comprising a coating, wherein thecoating is a non-uniform coating.

4056. The device of item 4021, further comprising a coating, wherein thecoating is a discontinuous coating.

4057. The device of item 4021, further comprising a coating, wherein thecoating is a patterned coating.

4058. The device of item 4021, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

4059. The device of item 4021, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

4060. The device of item 4021, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

4061. The device of item 4021, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

4062. The device of item 4021, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

4063. The device of item 4021, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

4064. The device of item 4021, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

4065. The device of item 4021, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

4066. The device of item 4021, further comprising a coating, wherein thecoating further comprises a polymer.

4067. The device of item 4021, further comprising a first coating havinga first composition and the second coating having a second composition.

4068. The device of item 4021, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

4069. The device of item 4021, further comprising a polymer.

4070. The device of item 4021, further comprising a polymeric carrier.

4071. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

4072. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

4073. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

4074. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

4075. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

4076. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

4077. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

4078. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

4079. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

4080. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

4081. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

4082. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

4083. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

4084. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

4085. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

4086. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

4087. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

4088. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

4089. The device of item 4021, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

4090. The device of item 4021, further comprising a lubricious coating.

4091. The device of item 4021 wherein the fibrosing agent is locatedwithin pores or holes of the device.

4092. The device of item 4021 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

4093. The device of item 4021, further comprising a secondpharmaceutically active agent.

4094. The device of item 4021, further comprising an anti-inflammatoryagent.

4095. The device of item 4021, further comprising an agent that inhibitsinfection.

4096. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

4097. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

4098. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

4099. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

4100. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

4101. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

4102. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

4103. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

4104. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

4105. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

4106. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

4107. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

4108. The device of item 4021, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

4109. The device of item 4021, further comprising an anti-thromboticagent.

4110. The device of item 4021, further comprising a visualization agent.

4111. The device of item 4021, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

4112. The device of item 4021, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

4113. The device of item 4021, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

4114. The device of item 4021, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

4115. The device of item 4021, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

4116. The device of item 4021, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

4117. The device of item 4021, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

4118. The device of item 4021, further comprising an echogenic material.

4119. The device of item 4021, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

4120. The device of item 4021 wherein the device is sterile.

4121. The device of item 4021 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

4122. The device of item 4021 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

4123. The device of item 4021 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

4124. The device of item 4021 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

4125. The device of item 4021 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

4126. The device of item 4021 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

4127. The device of item 4021 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

4128. The device of item 4021 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

4129. The device of item 4021 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

4130. The device of item 4021 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

4131. The device of item 4021 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

4132. The device of item 4021 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

4133. The device of item 4021 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

4134. The device of item 4021 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

4135. The device of item 4021 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

4136. The device of item 4021 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

4137. The device of item 4021 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

4138. The device of item 4021 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

4139. The device of item 4021 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

4140. The device of item 4021 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4141. The device of item 4021 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4142. The device of item 4021 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4143. The device of item 4021 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

4144. The device of item 4021 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4145. A medical device comprising an internal fixation implant and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

4146. The device of item 4145 wherein the fibrosing agent promotesregeneration.

4147. The device of item 4145 wherein the fibrosing agent promotesangiogenesis.

4148. The device of item 4145 wherein the fibrosing agent promotesfibroblast migration.

4149. The device of item 4145 wherein the fibrosing agent promotesfibroblast proliferation.

4150. The device of item 4145 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

4151. The device of item 4145 wherein the fibrosing agent promotestissue remodeling.

4152. The device of item 4145 wherein the fibrosing agent is an arterialvessel wall irritant.

4153. The device of item 4145 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4154. The device of item 4145 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4155. The device of item 4145 wherein the fibrosing agent is orcomprises silk.

4156. The device of item 4145 wherein the fibrosing agent is orcomprises mineral particles.

4157. The device of item 4145 wherein the fibrosing agent is orcomprises chitosan.

4158. The device of item 4145 wherein the fibrosing agent is orcomprises polylysine.

4159. The device of item 4145 wherein the fibrosing agent is orcomprises fibronectin.

4160. The device of item 4145 wherein the fibrosing agent is orcomprises bleomycin.

4161. The device of item 4145 wherein the fibrosing agent is orcomprises CTGF.

4162. The device of item 4145 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

4163. The device of item 4145 wherein the fibrosing agent is in the formof a particulate.

4164. The device of item 4145 wherein the composition further comprisesan inflammatory cytokine.

4165. The device of item 4145 wherein the composition further comprisesan agent that stimulates cell proliferation.

4166. The device of item 4145 wherein the composition is in the form ofa gel, paste, or spray.

4167. The device of item 4145 wherein the fibrosing agent is in the formof tufts.

4168. The device of item 4145, further comprising a polymer.

4169. The device of item 4145, further comprising a polymeric carrier.

4170. The device of item 4145 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4171. The device of item 4145 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4172. The device of item 4145, further comprising a coating, wherein thecoating comprises the fibrosing agent.

4173. The device of item 4145, further comprising a coating, wherein thecoating is disposed on a surface of the device.

4174. The device of item 4145, further comprising a coating, wherein thecoating directly contacts the device.

4175. The device of item 4145, further comprising a coating, wherein thecoating indirectly contacts the device.

4176. The device of item 4145, further comprising a coating, wherein thecoating partially covers the device.

4177. The device of item 4145, further comprising a coating, wherein thecoating completely covers the device.

4178. The device of item 4145, further comprising a coating, wherein thecoating is a uniform coating.

4179. The device of item 4145, further comprising a coating, wherein thecoating is a non-uniform coating.

4180. The device of item 4145, further comprising a coating, wherein thecoating is a discontinuous coating.

4181. The device of item 4145, further comprising a coating, wherein thecoating is a patterned coating.

4182. The device of item 4145, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

4183. The device of item 4145, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

4184. The device of item 4145, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

4185. The device of item 4145, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

4186. The device of item 4145, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

4187. The device of item 4145, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

4188. The device of item 4145, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

4189. The device of item 4145, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

4190. The device of item 4145, further comprising a coating, wherein thecoating further comprises a polymer.

4191. The device of item 4145, further comprising a first coating havinga first composition and the second coating having a second composition.

4192. The device of item 4145, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

4193. The device of item 4145, further comprising a polymer.

4194. The device of item 4145, further comprising a polymeric carrier.

4195. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

4196. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

4197. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

4198. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

4199. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

4200. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

4201. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

4202. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

4203. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

4204. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

4205. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

4206. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

4207. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

4208. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

4209. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

4210. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

4211. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

4212. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

4213. The device of item 4145, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

4214. The device of item 4145, further comprising a lubricious coating.

4215. The device of item 4145 wherein the fibrosing agent is locatedwithin pores or holes of the device.

4216. The device of item 4145 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

4217. The device of item 4145, further comprising a secondpharmaceutically active agent.

4218. The device of item 4145, further comprising an anti-inflammatoryagent.

4219. The device of item 4145, further comprising an agent that inhibitsinfection.

4220. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

4221. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

4222. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

4223. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

4224. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

4225. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

4226. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

4227. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

4228. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

4229. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

4230. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

4231. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

4232. The device of item 4145, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

4233. The device of item 4145, further comprising an anti-thromboticagent.

4234. The device of item 4145, further comprising a visualization agent.

4235. The device of item 4145, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

4236. The device of item 4145, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

4237. The device of item 4145, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

4238. The device of item 4145, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

4239. The device of item 4145, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

4240. The device of item 4145, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

4241. The device of item 4145, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

4242. The device of item 4145, further comprising an echogenic material.

4243. The device of item 4145, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

4244. The device of item 4145 wherein the device is sterile.

4245. The device of item 4145 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

4246. The device of item 4145 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

4247. The device of item 4145 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

4248. The device of item 4145 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

4249. The device of item 4145 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

4250. The device of item 4145 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

4251. The device of item 4145 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

4252. The device of item 4145 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

4253. The device of item 4145 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

4254. The device of item 4145 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

4255. The device of item 4145 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

4256. The device of item 4145 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

4257. The device of item 4145 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

4258. The device of item 4145 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

4259. The device of item 4145 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

4260. The device of item 4145 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

4261. The device of item 4145 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

4262. The device of item 4145 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

4263. The device of item 4145 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

4264. The device of item 4145 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4265. The device of item 4145 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4266. The device of item 4145 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4267. The device of item 4145 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

4268. The device of item 4145 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4269. A medical device comprising an external fixation implant and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

4270. The device of item 4269 wherein the fibrosing agent promotesregeneration.

4271. The device of item 4269 wherein the fibrosing agent promotesangiogenesis.

4272. The device of item 4269 wherein the fibrosing agent promotesfibroblast migration.

4273. The device of item 4269 wherein the fibrosing agent promotesfibroblast proliferation.

4274. The device of item 4269 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

4275. The device of item 4269 wherein the fibrosing agent promotestissue remodeling.

4276. The device of item 4269 wherein the fibrosing agent is an arterialvessel wall irritant.

4277. The device of item 4269 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4278. The device of item 4269 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4279. The device of item 4269 wherein the fibrosing agent is orcomprises silk.

4280. The device of item 4269 wherein the fibrosing agent is orcomprises mineral particles.

4281. The device of item 4269 wherein the fibrosing agent is orcomprises chitosan.

4282. The device of item 4269 wherein the fibrosing agent is orcomprises polylysine.

4283. The device of item 4269 wherein the fibrosing agent is orcomprises fibronectin.

4284. The device of item 4269 wherein the fibrosing agent is orcomprises bleomycin.

4285. The device of item 4269 wherein the fibrosing agent is orcomprises CTGF.

4286. The device of item 4269 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

4287. The device of item 4269 wherein the fibrosing agent is in the formof a particulate.

4288. The device of item 4269 wherein the composition further comprisesan inflammatory cytokine.

4289. The device of item 4269 wherein the composition further comprisesan agent that stimulates cell proliferation.

4290. The device of item 4269 wherein the composition is in the form ofa gel, paste, or spray.

4291. The device of item 4269 wherein the fibrosing agent is in the formof tufts.

4292. The device of item 4269, further comprising a polymer.

4293. The device of item 4269, further comprising a polymeric carrier.

4294. The device of item 4269 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4295. The device of item 4269 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4296. The device of item 4269, further comprising a coating, wherein thecoating comprises the fibrosing agent.

4297. The device of item 4269, further comprising a coating, wherein thecoating is disposed on a surface of the device.

4298. The device of item 4269, further comprising a coating, wherein thecoating directly contacts the device.

4299. The device of item 4269, further comprising a coating, wherein thecoating indirectly contacts the device.

4300. The device of item 4269, further comprising a coating, wherein thecoating partially covers the device.

4301. The device of item 4269, further comprising a coating, wherein thecoating completely covers the device.

4302. The device of item 4269, further comprising a coating, wherein thecoating is a uniform coating.

4303. The device of item 4269, further comprising a coating, wherein thecoating is a non-uniform coating.

4304. The device of item 4269, further comprising a coating, wherein thecoating is a discontinuous coating.

4305. The device of item 4269, further comprising a coating, wherein thecoating is a patterned coating.

4306. The device of item 4269, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

4307. The device of item 4269, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

4308. The device of item 4269, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

4309. The device of item 4269, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

4310. The device of item 4269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

4311. The device of item 4269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

4312. The device of item 4269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

4313. The device of item 4269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

4314. The device of item 4269, further comprising a coating, wherein thecoating further comprises a polymer.

4315. The device of item 4269, further comprising a first coating havinga first composition and the second coating having a second composition.

4316. The device of item 4269, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

4317. The device of item 4269, further comprising a polymer.

4318. The device of item 4269, further comprising a polymeric carrier.

4319. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

4320. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

4321. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

4322. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

4323. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

4324. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

4325. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

4326. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

4327. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

4328. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

4329. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

4330. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

4331. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

4332. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

4333. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

4334. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

4335. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

4336. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

4337. The device of item 4269, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

4338. The device of item 4269, further comprising a lubricious coating.

4339. The device of item 4269 wherein the fibrosing agent is locatedwithin pores or holes of the device.

4340. The device of item 4269 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

4341. The device of item 4269, further comprising a secondpharmaceutically active agent.

4342. The device of item 4269, further comprising an anti-inflammatoryagent.

4343. The device of item 4269, further comprising an agent that inhibitsinfection.

4344. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

4345. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

4346. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

4347. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

4348. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

4349. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

4350. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

4351. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

4352. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

4353. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

4354. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

4355. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

4356. The device of item 4269, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

4357. The device of item 4269, further comprising an anti-thromboticagent.

4358. The device of item 4269, further comprising a visualization agent.

4359. The device of item 4269, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

4360. The device of item 4269, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

4361. The device of item 4269, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

4362. The device of item 4269, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

4363. The device of item 4269, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

4364. The device of item 4269, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

4365. The device of item 4269, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

4366. The device of item 4269, further comprising an echogenic material.

4367. The device of item 4269, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

4368. The device of item 4269 wherein the device is sterile.

4369. The device of item 4269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

4370. The device of item 4269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

4371. The device of item 4269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

4372. The device of item 4269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

4373. The device of item 4269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

4374. The device of item 4269 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

4375. The device of item 4269 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

4376. The device of item 4269 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

4377. The device of item 4269 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

4378. The device of item 4269 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

4379. The device of item 4269 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

4380. The device of item 4269 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

4381. The device of item 4269 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

4382. The device of item 4269 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

4383. The device of item 4269 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

4384. The device of item 4269 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

4385. The device of item 4269 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

4386. The device of item 4269 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

4387. The device of item 4269 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

4388. The device of item 4269 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4389. The device of item 4269 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4390. The device of item 4269 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4391. The device of item 4269 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

4392. The device of item 4269 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4393. A medical device comprising a fixation screw and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

4394. The device of item 4393 wherein the fibrosing agent promotesregeneration.

4395. The device of item 4393 wherein the fibrosing agent promotesangiogenesis.

4396. The device of item 4393 wherein the fibrosing agent promotesfibroblast migration.

4397. The device of item 4393 wherein the fibrosing agent promotesfibroblast proliferation.

4398. The device of item 4393 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

4399. The device of item 4393 wherein the fibrosing agent promotestissue remodeling.

4400. The device of item 4393 wherein the fibrosing agent is an arterialvessel wall irritant.

4401. The device of item 4393 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4402. The device of item 4393 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4403. The device of item 4393 wherein the fibrosing agent is orcomprises silk.

4404. The device of item 4393 wherein the fibrosing agent is orcomprises mineral particles.

4405. The device of item 4393 wherein the fibrosing agent is orcomprises chitosan.

4406. The device of item 4393 wherein the fibrosing agent is orcomprises polylysine.

4407. The device of item 4393 wherein the fibrosing agent is orcomprises fibronectin.

4408. The device of item 4393 wherein the fibrosing agent is orcomprises bleomycin.

4409. The device of item 4393 wherein the fibrosing agent is orcomprises CTGF.

4410. The device of item 4393 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

4411. The device of item 4393 wherein the fibrosing agent is in the formof a particulate.

4412. The device of item 4393 wherein the composition further comprisesan inflammatory cytokine.

4413. The device of item 4393 wherein the composition further comprisesan agent that stimulates cell proliferation.

4414. The device of item 4393 wherein the composition is in the form ofa gel, paste, or spray.

4415. The device of item 4393 wherein the fibrosing agent is in the formof tufts.

4416. The device of item 4393, further comprising a polymer.

4417. The device of item 4393, further comprising a polymeric carrier.

4418. The device of item 4393 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4419. The device of item 4393 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4420. The device of item 4393, further comprising a coating, wherein thecoating comprises the fibrosing agent.

4421. The device of item 4393, further comprising a coating, wherein thecoating is disposed on a surface of the device.

4422. The device of item 4393, further comprising a coating, wherein thecoating directly contacts the device.

4423. The device of item 4393, further comprising a coating, wherein thecoating indirectly contacts the device.

4424. The device of item 4393, further comprising a coating, wherein thecoating partially covers the device.

4425. The device of item 4393, further comprising a coating, wherein thecoating completely covers the device.

4426. The device of item 4393, further comprising a coating, wherein thecoating is a uniform coating.

4427. The device of item 4393, further comprising a coating, wherein thecoating is a non-uniform coating.

4428. The device of item 4393, further comprising a coating, wherein thecoating is a discontinuous coating.

4429. The device of item 4393, further comprising a coating, wherein thecoating is a patterned coating.

4430. The device of item 4393, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

4431. The device of item 4393, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

4432. The device of item 4393, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

4433. The device of item 4393, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

4434. The device of item 4393, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

4435. The device of item 4393, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

4436. The device of item 4393, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

4437. The device of item 4393, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

4438. The device of item 4393, further comprising a coating, wherein thecoating further comprises a polymer.

4439. The device of item 4393, further comprising a first coating havinga first composition and the second coating having a second composition.

4440. The device of item 4393, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

4441. The device of item 4393, further comprising a polymer.

4442. The device of item 4393, further comprising a polymeric carrier.

4443. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

4444. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

4445. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

4446. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

4447. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

4448. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

4449. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

4450. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

4451. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

4452. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

4453. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

4454. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

4455. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

4456. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

4457. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

4458. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

4459. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

4460. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

4461. The device of item 4393, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

4462. The device of item 4393, further comprising a lubricious coating.

4463. The device of item 4393 wherein the fibrosing agent is locatedwithin pores or holes of the device.

4464. The device of item 4393 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

4465. The device of item 4393, further comprising a secondpharmaceutically active agent.

4466. The device of item 4393, further comprising an anti-inflammatoryagent.

4467. The device of item 4393, further comprising an agent that inhibitsinfection.

4468. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

4469. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

4470. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

4471. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

4472. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

4473. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

4474. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

4475. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

4476. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

4477. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

4478. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

4479. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

4480. The device of item 4393, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

4481. The device of item 4393, further comprising an anti-thromboticagent.

4482. The device of item 4393, further comprising a visualization agent.

4483. The device of item 4393, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

4484. The device of item 4393, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

4485. The device of item 4393, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

4486. The device of item 4393, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

4487. The device of item 4393, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

4488. The device of item 4393, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

4489. The device of item 4393, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

4490. The device of item 4393, further comprising an echogenic material.

4491. The device of item 4393, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

4492. The device of item 4393 wherein the device is sterile.

4493. The device of item 4393 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

4494. The device of item 4393 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

4495. The device of item 4393 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

4496. The device of item 4393 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

4497. The device of item 4393 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

4498. The device of item 4393 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

4499. The device of item 4393 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

4500. The device of item 4393 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

4501. The device of item 4393 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

4502. The device of item 4393 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

4503. The device of item 4393 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

4504. The device of item 4393 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

4505. The device of item 4393 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

4506. The device of item 4393 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

4507. The device of item 4393 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

4508. The device of item 4393 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

4509. The device of item 4393 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

4510. The device of item 4393 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

4511. The device of item 4393 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

4512. The device of item 4393 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4513. The device of item 4393 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4514. The device of item 4393 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4515. The device of item 4393 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

4516. The device of item 4393 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4517. The device of item 4393 wherein the fixation screw isbiodegradable.

4518. The device of item 4393 wherein the fixation screw isnon-biodegradable.

4519. A medical device comprising an interferential screw and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

4520. The device of item 4519 wherein the fibrosing agent promotesregeneration.

4521. The device of item 4519 wherein the fibrosing agent promotesangiogenesis.

4522. The device of item 4519 wherein the fibrosing agent promotesfibroblast migration.

4523. The device of item 4519 wherein the fibrosing agent promotesfibroblast proliferation.

4524. The device of item 4519 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

4525. The device of item 4519 wherein the fibrosing agent promotestissue remodeling.

4526. The device of item 4519 wherein the fibrosing agent is an arterialvessel wall irritant.

4527. The device of item 4519 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4528. The device of item 4519 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4529. The device of item 4519 wherein the fibrosing agent is orcomprises silk.

4530. The device of item 4519 wherein the fibrosing agent is orcomprises mineral particles.

4531. The device of item 4519 wherein the fibrosing agent is orcomprises chitosan.

4532. The device of item 4519 wherein the fibrosing agent is orcomprises polylysine.

4533. The device of item 4519 wherein the fibrosing agent is orcomprises fibronectin.

4534. The device of item 4519 wherein the fibrosing agent is orcomprises bleomycin.

4535. The device of item 4519 wherein the fibrosing agent is orcomprises CTGF.

4536. The device of item 4519 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

4537. The device of item 4519 wherein the fibrosing agent is in the formof a particulate.

4538. The device of item 4519 wherein the composition further comprisesan inflammatory cytokine.

4539. The device of item 4519 wherein the composition further comprisesan agent that stimulates cell proliferation.

4540. The device of item 4519 wherein the composition is in the form ofa gel, paste, or spray.

4541. The device of item 4519 wherein the fibrosing agent is in the formof tufts.

4542. The device of item 4519, further comprising a polymer.

4543. The device of item 4519, further comprising a polymeric carrier.

4544. The device of item 4519 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4545. The device of item 4519 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4546. The device of item 4519, further comprising a coating, wherein thecoating comprises the fibrosing agent.

4547. The device of item 4519, further comprising a coating, wherein thecoating is disposed on a surface of the device.

4548. The device-of item 4519, further comprising a coating, wherein thecoating directly contacts the device.

4549. The device of item 4519, further comprising a coating, wherein thecoating indirectly contacts the device.

4550. The device of item 4519, further comprising a coating, wherein thecoating partially covers the device.

4551. The device of item 4519, further comprising a coating, wherein thecoating completely covers the device.

4552. The device of item 4519, further comprising a coating, wherein thecoating is a uniform coating.

4553. The device of item 4519, further comprising a coating, wherein thecoating is a non-uniform coating.

4554. The device of item 4519, further comprising a coating, wherein thecoating is a discontinuous coating.

4555. The device of item 4519, further comprising a coating, wherein thecoating is a patterned coating.

4556. The device of item 4519, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

4557. The device of item 4519, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

4558. The device of item 4519, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

4559. The device of item 4519, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

4560. The device of item 4519, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

4561. The device of item 4519, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

4562. The device of item 4519, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

4563. The device of item 4519, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

4564. The device of item 4519, further comprising a coating, wherein thecoating further comprises a polymer.

4565. The device of item 4519, further comprising a first coating havinga first composition and the second coating having a second composition.

4566. The device of item 4519, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

4567. The device of item 4519, further comprising a polymer.

4568. The device of item 4519, further comprising a polymeric carrier.

4569. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

4570. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

4571. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

4572. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

4573. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

4574. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

4575. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

4576. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

4577. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

4578. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

4579. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

4580. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

4581. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

4582. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

4583. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

4584. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

4585. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

4586. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

4587. The device of item 4519, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

4588. The device of item 4519, further comprising a lubricious coating.

4589. The device of item 4519 wherein the fibrosing agent is locatedwithin pores or holes of the device.

4590. The device of item 4519 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

4591. The device of item 4519, further comprising a secondpharmaceutically active agent.

4592. The device of item 4519, further comprising an anti-inflammatoryagent.

4593. The device of item 4519, further comprising an agent that inhibitsinfection.

4594. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

4595. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

4596. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

4597. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

4598. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

4599. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

4600. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

4601. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

4602. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

4603. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

4604. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

4605. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

4606. The device of item 4519, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

4607. The device of item 4519, further comprising an anti-thromboticagent.

4608. The device of item 4519, further comprising a visualization agent.

4609. The device of item 4519, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

4610. The device of item 4519, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

4611. The device of item 4519, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

4612. The device of item 4519, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

4613. The device of item 4519, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

4614. The device of item 4519, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

4615. The device of item 4519, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

4616. The device of item 4519, further comprising an echogenic material.

4617. The device of item 4519, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

4618. The device of item 4519 wherein the device is sterile.

4619. The device of item 4519 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

4620. The device of item 4519 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

4621. The device of item 4519 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

4622. The device of item 4519 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

4623. The device of item 4519 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

4624. The device of item 4519 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

4625. The device of item 4519 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

4626. The device of item 4519 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

4627. The device of item 4519 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

4628. The device of item 4519 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

4629. The device of item 4519 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

4630. The device of item 4519 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

4631. The device of item 4519 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

4632. The device of item 4519 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

4633. The device of item 4519 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

4634. The device of item 4519 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

4635. The device of item 4519 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

4636. The device of item 4519 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

4637. The device of item 4519 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

4638. The device of item 4519 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4639. The device of item 4519 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4640. The device of item 4519 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4641. The device of item 4519 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

4642. The device of item 4519 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4643. The device of item 4519 wherein the interferential screw isdegradable.

4644. The device of item 4519 wherein the interferential screw isnon-degradable.

4645. A medical device comprising a trochanteric screw and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

4646. The device of item 4645 wherein the fibrosing agent promotesregeneration.

4647. The device of item 4645 wherein the fibrosing agent promotesangiogenesis.

4648. The device of item 4645 wherein the fibrosing agent promotesfibroblast migration.

4649. The device of item 4645 wherein the fibrosing agent promotesfibroblast proliferation.

4650. The device of item 4645 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

4651. The device of item 4645 wherein the fibrosing agent promotestissue remodeling.

4652. The device of item 4645 wherein the fibrosing agent is an arterialvessel wall irritant.

4653. The device of item 4645 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4654. The device of item 4645 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4655. The device of item 4645 wherein the fibrosing agent is orcomprises silk.

4656. The device of item 4645 wherein the fibrosing agent is orcomprises mineral particles.

4657. The device of item 4645 wherein the fibrosing agent is orcomprises chitosan.

4658. The device of item 4645 wherein the fibrosing agent is orcomprises polylysine.

4659. The device of item 4645 wherein the fibrosing agent is orcomprises fibronectin.

4660. The device of item 4645 wherein the fibrosing agent is orcomprises bleomycin.

4661. The device of item 4645 wherein the fibrosing agent is orcomprises CTGF.

4662. The device of item 4645 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

4663. The device of item 4645 wherein the fibrosing agent is in the formof a particulate.

4664. The device of item 4645 wherein the composition further comprisesan inflammatory cytokine.

4665. The device of item 4645 wherein the composition further comprisesan agent that stimulates cell proliferation.

4666. The device of item 4645 wherein the composition is in the form ofa gel, paste, or spray.

4667. The device of item 4645 wherein the fibrosing agent is in the formof tufts.

4668. The device of item 4645, further comprising a polymer.

4669. The device of item 4645, further comprising a polymeric carrier.

4670. The device of item 4645 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4671. The device of item 4645 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4672. The device of item 4645, further comprising a coating, wherein thecoating comprises the fibrosing agent.

4673. The device of item 4645, further comprising a coating, wherein thecoating is disposed on a surface of the device.

4674. The device of item 4645, further comprising a coating, wherein thecoating directly contacts the device.

4675. The device of item 4645, further comprising a coating, wherein thecoating indirectly contacts the device.

4676. The device of item 4645, further comprising a coating, wherein thecoating partially covers the device.

4677. The device of item 4645, further comprising a coating, wherein thecoating completely covers the device.

4678. The device of item 4645, further comprising a coating, wherein thecoating is a uniform coating.

4679. The device of item 4645, further comprising a coating, wherein thecoating is a non-uniform coating.

4680. The device of item 4645, further comprising a coating, wherein thecoating is a discontinuous coating.

4681. The device of item 4645, further comprising a coating, wherein thecoating is a patterned coating.

4682. The device of item 4645, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

4683. The device of item 4645, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

4684. The device of item 4645, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

4685. The device of item 4645, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

4686. The device of item 4645, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

4687. The device of item 4645, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

4688. The device of item 4645, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

4689. The device of item 4645, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

4690. The device of item 4645, further comprising a coating, wherein thecoating further comprises a polymer.

4691. The device of item 4645, further comprising a first coating havinga first composition and the second coating having a second composition.

4692. The device of item 4645, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

4693. The device of item 4645, further comprising a polymer.

4694. The device of item 4645, further comprising a polymeric carrier.

4695. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

4696. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

4697. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

4698. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

4699. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

4700. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

4701. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

4702. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

4703. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

4704. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

4705. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

4706. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

4707. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

4708. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

4709. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

4710. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

4711. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

4712. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

4713. The device of item 4645, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

4714. The device of item 4645, further comprising a lubricious coating.

4715. The device of item 4645 wherein the fibrosing agent is locatedwithin pores or holes of the device.

4716. The device of item 4645 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

4717. The device of item 4645, further comprising a secondpharmaceutically active agent.

4718. The device of item 4645, further comprising an anti-inflammatoryagent.

4719. The device of item 4645, further comprising an agent that inhibitsinfection.

4720. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

4721. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

4722. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

4723. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

4724. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

4725. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

4726. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

4727. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

4728. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

4729. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

4730. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

4731. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

4732. The device of item 4645, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

4733. The device of item 4645, further comprising an anti-thromboticagent.

4734. The device of item 4645, further comprising a visualization agent.

4735. The device of item 4645, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

4736. The device of item 4645, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

4737. The device of item 4645, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

4738. The device of item 4645, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

4739. The device of item 4645, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

4740. The device of item 4645, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

4741. The device of item 4645, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

4742. The device of item 4645, further comprising an echogenic material.

4743. The device of item 4645, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

4744. The device of item 4645 wherein the device is sterile.

4745. The device of item 4645 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

4746. The device of item 4645 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

4747. The device of item 4645 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

4748. The device of item 4645 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

4749. The device of item 4645 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

4750. The device of item 4645 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

4751. The device of item 4645 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

4752. The device of item 4645 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

4753. The device of item 4645 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

4754. The device of item 4645 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

4755. The device of item 4645 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

4756. The device of item 4645 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

4757. The device of item 4645 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

4758. The device of item 4645 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

4759. The device of item 4645 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

4760. The device of item 4645 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

4761. The device of item 4645 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

4762. The device of item 4645 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

4763. The device of item 4645 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

4764. The device of item 4645 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4765. The device of item 4645 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4766. The device of item 4645 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4767. The device of item 4645 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

4768. The device of item 4645 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4769. A medical device comprising a plate implant and a fibrosing agent,where the fibrosing agent induces a fibrotic response between the deviceand a patient in which the device is implanted.

4770. The device of item 4769 wherein the fibrosing agent promotesregeneration.

4771. The device of item 4769 wherein the fibrosing agent promotesangiogenesis.

4772. The device of item 4769 wherein the fibrosing agent promotesfibroblast migration.

4773. The device of item 4769 wherein the fibrosing agent promotesfibroblast proliferation.

4774. The device of item 4769 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

4775. The device of item 4769 wherein the fibrosing agent promotestissue remodeling.

4776. The device of item 4769 wherein the fibrosing agent is an arterialvessel wall irritant.

4777. The device of item 4769 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4778. The device of item 4769 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4779. The device of item 4769 wherein the fibrosing agent is orcomprises silk.

4780. The device of item 4769 wherein the fibrosing agent is orcomprises mineral particles.

4781. The device of item 4769 wherein the fibrosing agent is orcomprises chitosan.

4782. The device of item 4769 wherein the fibrosing agent is orcomprises polylysine.

4783. The device of item 4769 wherein the fibrosing agent is orcomprises fibronectin.

4784. The device of item 4769 wherein the fibrosing agent is orcomprises bleomycin.

4785. The device of item 4769 wherein the fibrosing agent is orcomprises CTGF.

4786. The device of item 4769 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

4787. The device of item 4769 wherein the fibrosing agent is in the formof a particulate.

4788. The device of item 4769 wherein the composition further comprisesan inflammatory cytokine.

4789. The device of item 4769 wherein the composition further comprisesan agent that stimulates cell proliferation.

4790. The device of item 4769 wherein the composition is in the form ofa gel, paste, or spray.

4791. The device of item 4769 wherein the fibrosing agent is in the formof tufts.

4792. The device of item 4769, further comprising a polymer.

4793. The device of item 4769, further comprising a polymeric carrier.

4794. The device of item 4769 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4795. The device of item 4769 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4796. The device of item 4769, further comprising a coating, wherein thecoating comprises the fibrosing agent.

4797. The device of item 4769, further comprising a coating, wherein thecoating is disposed on a surface of the device.

4798. The device of item 4769, further comprising a coating, wherein thecoating directly contacts the device.

4799. The device of item 4769, further comprising a coating, wherein thecoating indirectly contacts the device.

4800. The device of item 4769, further comprising a coating, wherein thecoating partially covers the device.

4801. The device of item 4769, further comprising a coating, wherein thecoating completely covers the device.

4802. The device of item 4769, further comprising a coating, wherein thecoating is a uniform coating.

4803. The device of item 4769, further comprising a coating, wherein thecoating is a non-uniform coating.

4804. The device of item 4769, further comprising a coating, wherein thecoating is a discontinuous coating.

4805. The device of item 4769, further comprising a coating, wherein thecoating is a patterned coating.

4806. The device of item 4769, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

4807. The device of item 4769, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

4808. The device of item 4769, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

4809. The device of item 4769, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

4810. The device of item 4769, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

4811. The device of item 4769, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

4812. The device of item 4769, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

4813. The device of item 4769, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

4814. The device of item 4769, further comprising a coating, wherein thecoating further comprises a polymer.

4815. The device of item 4769, further comprising a first coating havinga first composition and the second coating having a second composition.

4816. The device of item 4769, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

4817. The device of item 4769, further comprising a polymer.

4818. The device of item 4769, further comprising a polymeric carrier.

4819. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

4820. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

4821. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

4822. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

4823. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

4824. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

4825. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

4826. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

4827. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

4828. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

4829. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

4830. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

4831. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

4832. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

4833. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

4834. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

4835. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

4836. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

4837. The device of item 4769, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

4838. The device of item 4769, further comprising a lubricious coating.

4839. The device of item 4769 wherein the fibrosing agent is locatedwithin pores or holes of the device.

4840. The device of item 4769 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

4841. The device of item 4769, further comprising a secondpharmaceutically active agent.

4842. The device of item 4769, further comprising an anti-inflammatoryagent.

4843. The device of item 4769, further comprising an agent that inhibitsinfection.

4844. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

4845. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

4846. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

4847. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

4848. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

4849. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

4850. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

4851. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

4852. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

4853. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

4854. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

4855. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

4856. The device of item 4769, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

4857. The device of item 4769, further comprising an anti-thromboticagent.

4858. The device of item 4769, further comprising a visualization agent.

4859. The device of item 4769, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

4860. The device of item 4769, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

4861. The device of item 4769, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

4862. The device of item 4769, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

4863. The device of item 4769, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

4864. The device of item 4769, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

4865. The device of item 4769, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

4866. The device of item 4769, further comprising an echogenic material.

4867. The device of item 4769, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

4868. The device of item 4769 wherein the device is sterile.

4869. The device of item 4769 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

4870. The device of item 4769 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

4871. The device of item 4769 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

4872. The device of item 4769 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

4873. The device of item 4769 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

4874. The device of item 4769 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

4875. The device of item 4769 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

4876. The device of item 4769 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 190 days.

4877. The device of item 4769 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

4878. The device of item 4769 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

4879. The device of item 4769 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

4880. The device of item 4769 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

4881. The device of item 4769 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

4882. The device of item 4769 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

4883. The device of item 4769 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

4884. The device of item 4769 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

4885. The device of item 4769 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

4886. The device of item 4769 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

4887. The device of item 4769 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

4888. The device of item 4769 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4889. The device of item 4769 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4890. The device of item 4769 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4891. The device of item 4769 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

4892. The device of item 4769 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

4893. A medical device comprising a wire implant and a fibrosing agent,where the fibrosing agent induces a fibrotic response between the deviceand a patient in which the device is implanted.

4894. The device of item 4893 wherein the fibrosing agent promotesregeneration.

4895. The device of item 4893 wherein the fibrosing agent promotesangiogenesis.

4896. The device of item 4893 wherein the fibrosing agent promotesfibroblast migration.

4897. The device of item 4893 wherein the fibrosing agent promotesfibroblast proliferation.

4898. The device of item 4893 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

4899. The device of item 4893 wherein the fibrosing agent promotestissue remodeling.

4900. The device of item 4893 wherein the fibrosing agent is an arterialvessel wall irritant.

4901. The device of item 4893 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4902. The device of item 4893 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4903. The device of item 4893 wherein the fibrosing agent is orcomprises silk.

4904. The device of item 4893 wherein the fibrosing agent is orcomprises mineral particles.

4905. The device of item 4893 wherein the fibrosing agent is orcomprises chitosan.

4906. The device of item 4893 wherein the fibrosing agent is orcomprises polylysine.

4907. The device of item 4893 wherein the fibrosing agent is orcomprises fibronectin.

4908. The device of item 4893 wherein the fibrosing agent is orcomprises bleomycin.

4909. The device of item 4893 wherein the fibrosing agent is orcomprises CTGF.

4910. The device of item 4893 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

4911. The device of item 4893 wherein the fibrosing agent is in the formof a particulate.

4912. The device of item 4893 wherein the composition further comprisesan inflammatory cytokine.

4913. The device of item 4893 wherein the composition further comprisesan agent that stimulates cell proliferation.

4914. The device of item 4893 wherein the composition is in the form ofa gel, paste, or spray.

4915. The device of item 4893 wherein the fibrosing agent is in the formof tufts.

4916. The device of item 4893, further comprising a polymer.

4917. The device of item 4893, further comprising a polymeric carrier.

4918. The device of item 4893 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

4919. The device of item 4893 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

4920. The device of item 4893, further comprising a coating, wherein thecoating comprises the fibrosing agent.

4921. The device of item 4893, further comprising a coating, wherein thecoating is disposed on a surface of the device.

4922. The device of item 4893, further comprising a coating, wherein thecoating directly contacts the device.

4923. The device of item 4893, further comprising a coating, wherein thecoating indirectly contacts the device.

4924. The device of item 4893, further comprising a coating, wherein thecoating partially covers the device.

4925. The device of item 4893, further comprising a coating, wherein thecoating completely covers the device.

4926. The device of item 4893, further comprising a coating, wherein thecoating is a uniform coating.

4927. The device of item 4893, further comprising a coating, wherein thecoating is a non-uniform coating.

4928. The device of item 4893, further comprising a coating, wherein thecoating is a discontinuous coating.

4929. The device of item 4893, further comprising a coating, wherein thecoating is a patterned coating.

4930. The device of item 4893, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

4931. The device of item 4893, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

4932. The device of item 4893, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

4933. The device of item 4893, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

4934. The device of item 4893, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

4935. The device of item 4893, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

4936. The device of item 4893, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

4937. The device of item 4893, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

4938. The device of item 4893, further comprising a coating, wherein thecoating further comprises a polymer.

4939. The device of item 4893, further comprising a first coating havinga first composition and the second coating having a second composition.

4940. The device of item 4893, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

4941. The device of item 4893, further comprising a polymer.

4942. The device of item 4893, further comprising a polymeric carrier.

4943. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

4944. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

4945. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

4946. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

4947. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

4948. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

4949. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

4950. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

4951. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

4952. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

4953. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

4954. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

4955. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

4956. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

4957. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

4958. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

4959. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

4960. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

4961. The device of item 4893, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

4962. The device of item 4893, further comprising a lubricious coating.

4963. The device of item 4893 wherein the fibrosing agent is locatedwithin pores or holes of the device.

4964. The device of item 4893 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

4965. The device of item 4893, further comprising a secondpharmaceutically active agent.

4966. The device of item 4893, further comprising an anti-inflammatoryagent.

4967. The device of item 4893, further comprising an agent that inhibitsinfection.

4968. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

4969. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

4970. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

4971. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

4972. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

4973. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

4974. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

4975. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

4976. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

4977. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

4978. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

4979. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

4980. The device of item 4893, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

4981. The device of item 4893, further comprising an anti-thromboticagent.

4982. The device of item 4893, further comprising a visualization agent.

4983. The device of item 4893, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

4984. The device of item 4893, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

4985. The device of item 4893, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

4986. The device of item 4893, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

4987. The device of item 4893, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

4988. The device of item 4893, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

4989. The device of item 4893, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

4990. The device of item 4893, further comprising an echogenic material.

4991. The device of item 4893, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

4992. The device of item 4893 wherein the device is sterile.

4993. The device of item 4893 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

4994. The device of item 4893 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

4995. The device of item 4893 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

4996. The device of item 4893 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

4997. The device of item 4893 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

4998. The device of item 4893 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

4999. The device of item 4893 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

5000. The device of item 4893 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

5001. The device of item 4893 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

5002. The device of item 4893 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

5003. The device of item 4893 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

5004. The device of item 4893 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

5005. The device of item 4893 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

5006. The device of item 4893 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

5007. The device of item 4893 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

5008. The device of item 4893 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

5009. The device of item 4893 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

5010. The device of item 4893 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

5011. The device of item 4893 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

5012. The device of item 4893 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5013. The device of item 4893 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5014. The device of item 4893 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5015. The device of item 4893 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

5016. The device of item 4893 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5017. A medical device comprising a collagen implant and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

5018. The device of item 5017 wherein the fibrosing agent promotesregeneration.

5019. The device of item 5017 wherein the fibrosing agent promotesangiogenesis.

5020. The device of item 5017 wherein the fibrosing agent promotesfibroblast migration.

5021. The device of item 5017 wherein the fibrosing agent promotesfibroblast proliferation.

5022. The device of item 5017 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

5023. The device of item 5017 wherein the fibrosing agent promotestissue remodeling.

5024. The device of item 5017 wherein the fibrosing agent is an arterialvessel wall irritant.

5025. The device of item 5017 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5026. The device of item 5017 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5027. The device of item 5017 wherein the fibrosing agent is orcomprises silk.

5028. The device of item 5017 wherein the fibrosing agent is orcomprises mineral particles.

5029. The device of item 5017 wherein the fibrosing agent is orcomprises chitosan.

5030. The device of item 5017 wherein the fibrosing agent is orcomprises polylysine.

5031. The device of item 5017 wherein the fibrosing agent is orcomprises fibronectin.

5032. The device of item 5017 wherein the fibrosing agent is orcomprises bleomycin.

5033. The device of item 5017 wherein the fibrosing agent is orcomprises CTGF.

5034. The device of item 5017 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

5035. The device of item 5017 wherein the fibrosing agent is in the formof a particulate.

5036. The device of item 5017 wherein the composition further comprisesan inflammatory cytokine.

5037. The device of item 5017 wherein the composition further comprisesan agent that stimulates cell proliferation.

5038. The device of item 5017 wherein the composition is in the form ofa gel, paste, or spray.

5039. The device of item 5017 wherein the fibrosing agent is in the formof tufts.

5040. The device of item 5017, further comprising a polymer.

5041. The device of item 5017, further comprising a polymeric carrier.

5042. The device of item 5017 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5043. The device of item 5017 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5044. The device of item 5017, further comprising a coating, wherein thecoating comprises the fibrosing agent.

5045. The device of item 5017, further comprising a coating, wherein thecoating is disposed on a surface of the device.

5046. The device of item 5017, further comprising a coating, wherein thecoating directly contacts the device.

5047. The device of item 5017, further comprising a coating, wherein thecoating indirectly contacts the device.

5048. The device of item 5017, further comprising a coating, wherein thecoating partially covers the device.

5049. The device of item 5017, further comprising a coating, wherein thecoating completely covers the device.

5050. The device of item 5017, further comprising a coating, wherein thecoating is a uniform coating.

5051. The device of item 5017, further comprising a coating, wherein thecoating is a non-uniform coating.

5052. The device of item 5017, further comprising a coating, wherein thecoating is a discontinuous coating.

5053. The device of item 5017, further comprising a coating, wherein thecoating is a patterned coating.

5054. The device of item 5017, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

5055. The device of item 5017, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

5056. The device of item 5017, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

5057. The device of item 5017, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

5058. The device of item 5017, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

5059. The device of item 5017, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

5060. The device of item 5017, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

5061. The device of item 5017, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

5062. The device of item 5017, further comprising a coating, wherein thecoating further comprises a polymer.

5063. The device of item 5017, further comprising a first coating havinga first composition and the second coating having a second composition.

5064. The device of item 5017, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

5065. The device of item 5017, further comprising a polymer.

5066. The device of item 5017, further comprising a polymeric carrier.

5067. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

5068. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

5069. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

5070. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

5071. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

5072. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

5073. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

5074. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

5075. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

5076. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

5077. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

5078. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

5079. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

5080. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

5081. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

5082. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

5083. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

5084. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

5085. The device of item 5017, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

5086. The device of item 5017, further comprising a lubricious coating.

5087. The device of item 5017 wherein the fibrosing agent is locatedwithin pores or holes of the device.

5088. The device of item 5017 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

5089. The device of item 5017, further comprising a secondpharmaceutically active agent.

5090. The device of item 5017, further comprising an anti-inflammatoryagent.

5091. The device of item 5017, further comprising an agent that inhibitsinfection.

5092. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

5093. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

5094. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

5095. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

5096. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

5097. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

5098. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

5099. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

5100. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

5101. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

5102. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

5103. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

5104. The device of item 5017, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

5105. The device of item 5017, further comprising an anti-thromboticagent.

5106. The device of item 5017, further comprising a visualization agent.

5107. The device of item 5017, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

5108. The device of item 5017, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

5109. The device of item 5017, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

5110. The device of item 5017, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

5111. The device of item 5017, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

5112. The device of item 5017, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

5113. The device of item 5017, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

5114. The device of item 5017, further comprising an echogenic material.

5115. The device of item 5017, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

5116. The device of item 5017 wherein the device is sterile.

5117. The device of item 5017 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

5118. The device of item 5017 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

5119. The device of item 5017 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

5120. The device of item 5017 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

5121. The device of item 5017 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

5122. The device of item 5017 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

5123. The device of item 5017 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

5124. The device of item 5017 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

5125. The device of item 5017 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

5126. The device of item 5017 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

5127. The device of item 5017 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

5128. The device of item 5017 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

5129. The device of item 5017 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

5130. The device of item 5017 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

5131. The device of item 5017 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

5132. The device of item 5017 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

5133. The device of item 5017 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

5134. The device of item 5017 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

5135. The device of item 5017 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

5136. The device of item 5017 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5137. The device of item 5017 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5138. The device of item 5017 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5139. The device of item 5017 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

5140. The device of item 5017 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5141. A medical device comprising a Fallopian tube implant and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

5142. The device of item 5141 wherein the fibrosing agent promotesregeneration.

5143. The device of item 5141 wherein the fibrosing agent promotesangiogenesis.

5144. The device of item 5141 wherein the fibrosing agent promotesfibroblast migration.

5145. The device of item 5141 wherein the fibrosing agent promotesfibroblast proliferation.

5146. The device of item 5141 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

5147. The device of item 5141 wherein the fibrosing agent promotestissue remodeling.

5148. The device of item 5141 wherein the fibrosing agent is an arterialvessel wall irritant.

5149. The device of item 5141 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5150. The device of item 5141 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5151. The device of item 5141 wherein the fibrosing agent is orcomprises silk.

5152. The device of item 5141 wherein the fibrosing agent is orcomprises mineral particles.

5153. The device of item 5141 wherein the fibrosing agent is orcomprises chitosan.

5154. The device of item 5141 wherein the fibrosing agent is orcomprises polylysine.

5155. The device of item 5141 wherein the fibrosing agent is orcomprises fibronectin.

5156. The device of item 5141 wherein the fibrosing agent is orcomprises bleomycin.

5157. The device of item 5141 wherein the fibrosing agent is orcomprises CTGF.

5158. The device of item 5141 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

5159. The device of item 5141 wherein the fibrosing agent is in the formof a particulate.

5160. The device of item 5141 wherein the composition further comprisesan inflammatory cytokine.

5161. The device of item 5141 wherein the composition further comprisesan agent that stimulates cell proliferation.

5162. The device of item 5141 wherein the composition is in the form ofa gel, paste, or spray.

5163. The device of item 5141 wherein the fibrosing agent is in the formof tufts.

5164. The device of item 5141, further comprising a polymer.

5165. The device of item 5141, further comprising a polymeric carrier.

5166. The device of item 5141 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5167. The device of item 5141 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5168. The device of item 5141, further comprising a coating, wherein thecoating comprises the fibrosing agent.

5169. The device of item 5141, further comprising a coating, wherein thecoating is disposed on a surface of the device.

5170. The device of item 5141, further comprising a coating, wherein thecoating directly contacts the device.

5171. The device of item 5141, further comprising a coating, wherein thecoating indirectly contacts the device.

5172. The device of item 5141, further comprising a coating, wherein thecoating partially covers the device.

5173. The device of item 5141, further comprising a coating, wherein thecoating completely covers the device.

5174. The device of item 5141, further comprising a coating, wherein thecoating is a uniform coating.

5175. The device of item 5141, further comprising a coating, wherein thecoating is a non-uniform coating.

5176. The device of item 5141, further comprising a coating, wherein thecoating is a discontinuous coating.

5177. The device of item 5141, further comprising a coating, wherein thecoating is a patterned coating.

5178. The device of item 5141, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

5179. The device of item 5141, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

5180. The device of item 5141, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

5181. The device of item 5141, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

5182. The device of item 5141, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

5183. The device of item 5141, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

5184. The device of item 5141, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

5185. The device of item 5141, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

5186. The device of item 5141, further comprising a coating, wherein thecoating further comprises a polymer.

5187. The device of item 5141, further comprising a first coating havinga first composition and the second coating having a second composition.

5188. The device of item 5141, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

5189. The device of item 5141, further comprising a polymer.

5190. The device of item 5141, further comprising a polymeric carrier.

5191. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

5192. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

5193. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

5194. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

5195. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

5196. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

5197. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

5198. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

5199. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

5200. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

5201. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

5202. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

5203. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

5204. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

5205. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

5206. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

5207. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

5208. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

5209. The device of item 5141, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

5210. The device of item 5141, further comprising a lubricious coating.

5211. The device of item 5141 wherein the fibrosing agent is locatedwithin pores or holes of the device.

5212. The device of item 5141 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

5213. The device of item 5141, further comprising a secondpharmaceutically active agent.

5214. The device of item 5141, further comprising an anti-inflammatoryagent.

5215. The device of item 5141, further comprising an agent that inhibitsinfection.

5216. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

5217. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

5218. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

5219. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

5220. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

5221. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

5222. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

5223. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

5224. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

5225. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

5226. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

5227. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

5228. The device of item 5141, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

5229. The device of item 5141, further comprising an anti-thromboticagent.

5230. The device of item 5141, further comprising a visualization agent.

5231. The device of item 5141, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

5232. The device of item 5141, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

5233. The device of item 5141, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

5234. The device of item 5141, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

5235. The device of item 5141, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

5236. The device of item 5141, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

5237. The device of item 5141, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

5238. The device of item 5141, further comprising an echogenic material.

5239. The device of item 5141, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

5240. The device of item 5141 wherein the device is sterile.

5241. The device of item 5141 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

5242. The device of item 5141 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

5243. The device of item 5141 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

5244. The device of item 5141 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

5245. The device of item 5141 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

5246. The device of item 5141 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

5247. The device of item 5141 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

5248. The device of item 5141 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

5249. The device of item 5141 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

5250. The device of item 5141 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

5251. The device of item 5141 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

5252. The device of item 5141 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

5253. The device of item 5141 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

5254. The device of item 5141 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

5255. The device of item 5141 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

5256. The device of item 5141 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

5257. The device of item 5141 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

5258. The device of item 5141 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

5259. The device of item 5141 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

5260. The device of item 5141 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5261. The device of item 5141 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5262. The device of item 5141 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5263. The device of item 5141 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

5264. The device of item 5141 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5265. The device of item 5141 wherein the fallopian tube implant isinjectable.

5266. The device of item 5141 wherein the fallopian tube implant is anfallopian tumbe occlusive wire.

5267. The device of item 5141 wherein the fallopian tube implant is acoil fallopian tube implants.

5268. The device of item 5141 wherein the fallopian tube implant is acontraceptive uterine implant.

5269. A medical device comprising a transcatheter occluding implant anda fibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

5270. The device of item 5269 wherein the fibrosing agent promotesregeneration.

5271. The device of item 5269 wherein the fibrosing agent promotesangiogenesis.

5272. The device of item 5269 wherein the fibrosing agent promotesfibroblast migration.

5273. The device of item 5269 wherein the fibrosing agent promotesfibroblast proliferation.

5274. The device of item 5269 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

5275. The device of item 5269 wherein the fibrosing agent promotestissue remodeling.

5276. The device of item 5269 wherein the fibrosing agent is an arterialvessel wall irritant.

5277. The device of item 5269 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5278. The device of item 5269 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5279. The device of item 5269 wherein the fibrosing agent is orcomprises silk.

5280. The device of item 5269 wherein the fibrosing agent is orcomprises mineral particles.

5281. The device of item 5269 wherein the fibrosing agent is orcomprises chitosan.

5282. The device of item 5269 wherein the fibrosing agent is orcomprises polylysine.

5283. The device of item 5269 wherein the fibrosing agent is orcomprises fibronectin.

5284. The device of item 5269 wherein the fibrosing agent is orcomprises bleomycin.

5285. The device of item 5269 wherein the fibrosing agent is orcomprises CTGF.

5286. The device of item 5269 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

5287. The device of item 5269 wherein the fibrosing agent is in the formof a particulate.

5288. The device of item 5269 wherein the composition further comprisesan inflammatory cytokine.

5289. The device of item 5269 wherein the composition further comprisesan agent that stimulates cell proliferation.

5290. The device of item 5269 wherein the composition is in the form ofa gel, paste, or spray.

5291. The device of item 5269 wherein the fibrosing agent is in the formof tufts.

5292. The device of item 5269, further comprising a polymer.

5293. The device of item 5269, further comprising a polymeric carrier.

5294. The device of item 5269 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5295. The device of item 5269 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5296. The device of item 5269, further comprising a coating, wherein thecoating comprises the fibrosing agent.

5297. The device of item 5269, further comprising a coating, wherein thecoating is disposed on a surface of the device.

5298. The device of item 5269, further comprising a coating, wherein thecoating directly contacts the device.

5299. The device of item 5269, further comprising a coating, wherein thecoating indirectly contacts the device.

5300. The device of item 5269, further comprising a coating, wherein thecoating partially covers the device.

5301. The device of item 5269, further comprising a coating, wherein thecoating completely covers the device.

5302. The device of item 5269, further comprising a coating, wherein thecoating is a uniform coating.

5303. The device of item 5269, further comprising a coating, wherein thecoating is a non-uniform coating.

5304. The device of item 5269, further comprising a coating, wherein thecoating is a discontinuous coating.

5305. The device of item 5269, further comprising a coating, wherein thecoating is a patterned coating.

5306. The device of item 5269, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

5307. The device of item 5269, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

5308. The device of item 5269, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

5309. The device of item 5269, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

5310. The device of item 5269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

5311. The device of item 5269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

5312. The device of item 5269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

5313. The device of item 5269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

5314. The device of item 5269, further comprising a coating, wherein thecoating further comprises a polymer.

5315. The device of item 5269, further comprising a first coating havinga first composition and the second coating having a second composition.

5316. The device of item 5269, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

5317. The device of item 5269, further comprising a polymer.

5318. The device of item 5269, further comprising a polymeric carrier.

5319. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

5320. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

5321. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

5322. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

5323. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

5324. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

5325. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

5326. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

5327. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

5328. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

5329. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

5330. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

5331. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

5332. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

5333. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

5334. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

5335. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

5336. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

5337. The device of item 5269, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

5338. The device of item 5269, further comprising a lubricious coating.

5339. The device of item 5269 wherein the fibrosing agent is locatedwithin pores or holes of the device.

5340. The device of item 5269 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

5341. The device of item 5269, further comprising a secondpharmaceutically active agent.

5342. The device of item 5269, further comprising an anti-inflammatoryagent.

5343. The device of item 5269, further comprising an agent that inhibitsinfection.

5344. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

5345. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

5346. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

5347. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

5348. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

5349. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

5350. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

5351. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

5352. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

5353. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

5354. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

5355. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

5356. The device of item 5269, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

5357. The device of item 5269, further comprising an anti-thromboticagent.

5358. The device of item 5269, further comprising a visualization agent.

5359. The device of item 5269, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

5360. The device of item 5269, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

5361. The device of item 5269, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

5362. The device of item 5269, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

5363. The device of item 5269, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

5364. The device of item 5269, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

5365. The device of item 5269, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

5366. The device of item 5269, further comprising an echogenic material.

5367. The device of item 5269, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

5368. The device of item 5269 wherein the device is sterile.

5369. The device of item 5269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

5370. The device of item 5269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

5371. The device of item 5269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

5372. The device of item 5269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

5373. The device of item 5269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

5374. The device of item 5269 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

5375. The device of item 5269 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

5376. The device of item 5269 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

5377. The device of item 5269 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

5378. The device of item 5269 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

5379. The device of item 5269 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

5380. The device of item 5269 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

5381. The device of item 5269 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

5382. The device of item 5269 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

5383. The device of item 5269 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

5384. The device of item 5269 wherein the device comprises about 10 mgto about 0.250 mg of the fibrosing agent.

5385. The device of item 5269 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

5386. The device of item 5269 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

5387. The device of item 5269 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

5388. The device of item 5269 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5389. The device of item 5269 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5390. The device of item 5269 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5391. The device of item 5269 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

5392. The device of item 5269 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5393. A medical device comprising a prosthetic anal sphincter and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

5394. The device of item 5393 wherein the fibrosing agent promotesregeneration.

5395. The device of item 5393 wherein the fibrosing agent promotesangiogenesis.

5396. The device of item 5393 wherein the fibrosing agent promotesfibroblast migration.

5397. The device of item 5393 wherein the fibrosing agent promotesfibroblast proliferation.

5398. The device of item 5393 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

5399. The device of item 5393 wherein the fibrosing agent promotestissue remodeling.

5400. The device of item 5393 wherein the fibrosing agent is an arterialvessel wall irritant.

5401. The device of item 5393 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5402. The device of item 5393 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5403. The device of item 5393 wherein the fibrosing agent is orcomprises silk.

5404. The device of item 5393 wherein the fibrosing agent is orcomprises mineral particles.

5405. The device of item 5393 wherein the fibrosing agent is orcomprises chitosan.

5406. The device of item 5393 wherein the fibrosing agent is orcomprises polylysine.

5407. The device of item 5393 wherein the fibrosing agent is orcomprises fibronectin.

5408. The device of item 5393 wherein the fibrosing agent is orcomprises bleomycin.

5409. The device of item 5393 wherein the fibrosing agent is orcomprises CTGF.

5410. The device of item 5393 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

5411. The device of item 5393 wherein the fibrosing agent is in the formof a particulate.

5412. The device of item 5393 wherein the composition further comprisesan inflammatory cytokine.

5413. The device of item 5393 wherein the composition further comprisesan agent that stimulates cell proliferation.

5414. The device of item 5393 wherein the composition is in the form ofa gel, paste, or spray.

5415. The device of item 5393 wherein the fibrosing agent is in the formof tufts.

5416. The device of item 5393, further comprising a polymer.

5417. The device of item 5393, further comprising a polymeric carrier.

5418. The device of item 5393 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5419. The device of item 5393 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5420. The device of item 5393, further comprising a coating, wherein thecoating comprises the fibrosing agent.

5421. The device of item 5393, further comprising a coating, wherein thecoating is disposed on a surface of the device.

5422. The device of item 5393, further comprising a coating, wherein thecoating directly contacts the device.

5423. The device of item 5393, further comprising a coating, wherein thecoating indirectly contacts the device.

5424. The device of item 5393, further comprising a coating, wherein thecoating partially covers the device.

5425. The device of item 5393, further comprising a coating, wherein thecoating completely covers the device.

5426. The device of item 5393, further comprising a coating, wherein thecoating is a uniform coating.

5427. The device of item 5393, further comprising a coating, wherein thecoating is a non-uniform coating.

5428. The device of item 5393, further comprising a coating, wherein thecoating is a discontinuous coating.

5429. The device of item 5393, further comprising a coating, wherein thecoating is a patterned coating.

5430. The device of item 5393, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

5431. The device of item 5393, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

5432. The device of item 5393, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

5433. The device of item 5393, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

5434. The device of item 5393, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

5435. The device of item 5393, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

5436. The device of item 5393, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

5437. The device of item 5393, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

5438. The device of item 5393, further comprising a coating, wherein thecoating further comprises a polymer.

5439. The device of item 5393, further comprising a first coating havinga first composition and the second coating having a second composition.

5440. The device of item 5393, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

5441. The device of item 5393, further comprising a polymer.

5442. The device of item 5393, further comprising a polymeric carrier.

5443. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

5444. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

5445. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

5446. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

5447. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

5448. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

5449. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

5450. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

5451. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

5452. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

5453. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

5454. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

5455. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

5456. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

5457. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

5458. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

5459. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

5460. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

5461. The device of item 5393, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

5462. The device of item 5393, further comprising a lubricious coating.

5463. The device of item 5393 wherein the fibrosing agent is locatedwithin pores or holes of the device.

5464. The device of item 5393 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

5465. The device of item 5393, further comprising a secondpharmaceutically active agent.

5466. The device of item 5393, further comprising an anti-inflammatoryagent.

5467. The device of item 5393, further comprising an agent that inhibitsinfection.

5468. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

5469. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

5470. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

5471. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

5472. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

5473. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

5474. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

5475. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

5476. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

5477. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

5478. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

5479. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

5480. The device of item 5393, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

5481. The device of item 5393, further comprising an anti-thromboticagent.

5482. The device of item 5393, further comprising a visualization agent.

5483. The device of item 5393, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

5484. The device of item 5393, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

5485. The device of item 5393, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

5486. The device of item 5393, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

5487. The device of item 5393, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

5488. The device of item 5393, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

5489. The device of item 5393, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

5490. The device of item 5393, further comprising an echogenic material.

5491. The device of item 5393, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

5492. The device of item 5393 wherein the device is sterile.

5493. The device of item 5393 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

5494. The device of item 5393 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

5495. The device of item 5393 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

5496. The device of item 5393 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

5497. The device of item 5393 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

5498. The device of item 5393 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

5499. The device of item 5393 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

5500. The device of item 5393 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

5501. The device of item 5393 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

5502. The device of item 5393 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

5503. The device of item 5393 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

5504. The device of item 5393 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

5505. The device of item 5393 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

5506. The device of item 5393 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

5507. The device of item 5393 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

5508. The device of item 5393 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

5509. The device of item 5393 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

5510. The device of item 5393 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

5511. The device of item 5393 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

5512. The device of item 5393 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5513. The device of item 5393 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5514. The device of item 5393 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5515. The device of item 5393 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

5516. The device of item 5393 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5517. A medical device comprising a Fallopian tube stent and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

5518. The device of item 5517 wherein the fibrosing agent promotesregeneration.

5519. The device of item 5517 wherein the fibrosing agent promotesangiogenesis.

5520. The device of item 5517 wherein the fibrosing agent promotesfibroblast migration.

5521. The device of item 5517 wherein the fibrosing agent promotesfibroblast proliferation.

5522. The device of item 5517 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

5523. The device of item 5517 wherein the fibrosing agent promotestissue remodeling.

5524. The device of item 5517 wherein the fibrosing agent is an arterialvessel wall irritant.

5525. The device of item 5517 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5526. The device of item 5517 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5527. The device of item 5517 wherein the fibrosing agent is orcomprises silk.

5528. The device of item 5517 wherein the fibrosing agent is orcomprises mineral particles.

5529. The device of item 5517 wherein the fibrosing agent is orcomprises chitosan.

5530. The device of item 5517 wherein the fibrosing agent is orcomprises polylysine.

5531. The device of item 5517 wherein the fibrosing agent is orcomprises fibronectin.

5532. The device of item 5517 wherein the fibrosing agent is orcomprises bleomycin.

5533. The device of item 5517 wherein the fibrosing agent is orcomprises CTGF.

5534. The device of item 5517 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

5535. The device of item 5517 wherein the fibrosing agent is in the formof a particulate.

5536. The device of item 5517 wherein the composition further comprisesan inflammatory cytokine.

5537. The device of item 5517 wherein the composition further comprisesan agent that stimulates cell proliferation.

5538. The device of item 5517 wherein the composition is in the form ofa gel, paste, or spray.

5539. The device of item 5517 wherein the fibrosing agent is in the formof tufts.

5540. The device of item 5517, further comprising a polymer.

5541. The device of item 5517, further comprising a polymeric carrier.

5542. The device of item 5517 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5543. The device of item 5517 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5544. The device of item 5517, further comprising a coating, wherein thecoating comprises the fibrosing agent.

5545. The device of item 5517, further comprising a coating, wherein thecoating is disposed on a surface of the device.

5546. The device of item 5517, further comprising a coating, wherein thecoating directly contacts the device.

5547. The device of item 5517, further comprising a coating, wherein thecoating indirectly contacts the device.

5548. The device of item 5517, further comprising a coating, wherein thecoating partially covers the device.

5549. The device of item 5517, further comprising a coating, wherein thecoating completely covers the device.

5550. The device of item 5517, further comprising a coating, wherein thecoating is a uniform coating.

5551. The device of item 5517, further comprising a coating, wherein thecoating is a non-uniform coating.

5552. The device of item 5517, further comprising a coating, wherein thecoating is a discontinuous coating.

5553. The device of item 5517, further comprising a coating, wherein thecoating is a patterned coating.

5554. The device of item 5517, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

5555. The device of item 5517, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

5556. The device of item 5517, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

5557. The device of item 5517, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

5558. The device of item 5517, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

5559. The device of item 5517, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

5560. The device of item 5517, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

5561. The device of item 5517, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

5562. The device of item 5517, further comprising a coating, wherein thecoating further comprises a polymer.

5563. The device of item 5517, further comprising a first coating havinga first composition and the second coating having a second composition.

5564. The device of item 5517, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

5565. The device of item 5517, further comprising a polymer.

5566. The device of item 5517, further comprising a polymeric carrier.

5567. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

5568. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

5569. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

5570. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

5571. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

5572. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

5573. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

5574. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

5575. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

5576. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

5577. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

5578. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

5579. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

5580. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

5581. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

5582. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

5583. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

5584. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

5585. The device of item 5517, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

5586. The device of item 5517, further comprising a lubricious coating.

5587. The device of item 5517 wherein the fibrosing agent is locatedwithin pores or holes of the device.

5588. The device of item 5517 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

5589. The device of item 5517, further comprising a secondpharmaceutically active agent.

5590. The device of item 5517, further comprising an anti-inflammatoryagent.

5591. The device of item 5517, further comprising an agent that inhibitsinfection.

5592. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

5593. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

5594. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

5595. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

5596. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

5597. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

5598. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

5599. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

5600. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

5601. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

5602. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

5603. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

5604. The device of item 5517, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

5605. The device of item 5517, further comprising an anti-thromboticagent.

5606. The device of item 5517, further comprising a visualization agent.

5607. The device of item 5517, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

5608. The device of item 5517, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

5609. The device of item 5517, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

5610. The device of item 5517, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

5611. The device of item 5517, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

5612. The device of item 5517, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

5613. The device of item 5517, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

5614. The device of item 5517, further comprising an echogenic material.

5615. The device of item 5517, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

5616. The device of item 5517 wherein the device is sterile.

5617. The device of item 5517 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

5618. The device of item 5517 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

5619. The device of item 5517 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

5620. The device of item 5517 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

5621. The device of item 5517 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

5622. The device of item 5517 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

5623. The device of item 5517 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

5624. The device of item 5517 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

5625. The device of item 5517 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

5626. The device of item 5517 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

5627. The device of item 5517 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

5628. The device of item 5517 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

5629. The device of item 5517 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

5630. The device of item 5517 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

5631. The device of item 5517 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

5632. The device of item 5517 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

5633. The device of item 5517 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

5634. The device of item 5517 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

5635. The device of item 5517 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

5636. The device of item 5517 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5637. The device of item 5517 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5638. The device of item 5517 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5639. The device of item 5517 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

5640. The device of item 5517 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5641. A medical device comprising a Vas Deferens implant and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

5642. The device of item 5641 wherein the fibrosing agent promotesregeneration.

5643. The device of item 5641 wherein the fibrosing agent promotesangiogenesis.

5644. The device of item 5641 wherein the fibrosing agent promotesfibroblast migration.

5645. The device of item 5641 wherein the fibrosing agent promotesfibroblast proliferation.

5646. The device of item 5641 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

5647. The device of item 5641 wherein the fibrosing agent promotestissue remodeling.

5648. The device of item 5641 wherein the fibrosing agent is an arterialvessel wall irritant.

5649. The device of item 5641 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5650. The device of item 5641 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5651. The device of item 5641 wherein the fibrosing agent is orcomprises silk.

5652. The device of item 5641 wherein the fibrosing agent is orcomprises mineral particles.

5653. The device of item 5641 wherein the fibrosing agent is orcomprises chitosan.

5654. The device of item 5641 wherein the fibrosing agent is orcomprises polylysine.

5655. The device of item 5641 wherein the fibrosing agent is orcomprises fibronectin.

5656. The device of item 5641 wherein the fibrosing agent is orcomprises bleomycin.

5657. The device of item 5641 wherein the fibrosing agent is orcomprises CTGF.

5658. The device of item 5641 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

5659. The device of item 5641 wherein the fibrosing agent is in the formof a particulate.

5660. The device of item 5641 wherein the composition further comprisesan inflammatory cytokine.

5661. The device of item 5641 wherein the composition further comprisesan agent that stimulates cell proliferation.

5662. The device of item 5641 wherein the composition is in the form ofa gel, paste, or spray.

5663. The device of item 5641 wherein the fibrosing agent is in the formof tufts.

5664. The device of item 5641, further comprising a polymer.

5665. The device of item 5641, further comprising a polymeric carrier.

5666. The device of item 5641 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5667. The device of item 5641 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5668. The device of item 5641, further comprising a coating, wherein thecoating comprises the fibrosing agent.

5669. The device of item 5641, further comprising a coating, wherein thecoating is disposed on a surface of the device.

5670. The device of item 5641, further comprising a coating, wherein thecoating directly contacts the device.

5671. The device of item 5641, further comprising a coating, wherein thecoating indirectly contacts the device.

5672. The device of item 5641, further comprising a coating, wherein thecoating partially covers the device.

5673. The device of item 5641, further comprising a coating, wherein thecoating completely covers the device.

5674. The device of item 5641, further comprising a coating, wherein thecoating is a uniform coating.

5675. The device of item 5641, further comprising a coating, wherein thecoating is a non-uniform coating.

5676. The device of item 5641, further comprising a coating, wherein thecoating is a discontinuous coating.

5677. The device of item 5641, further comprising a coating, wherein thecoating is a patterned coating.

5678. The device of item 5641, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

5679. The device of item 5641, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

5680. The device of item 5641, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

5681. The device of item 5641, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

5682. The device of item 5641, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

5683. The device of item 5641, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.,

-   -   5684. The device of item 5641, further comprising a coating,        wherein the fibrosing agent is present in the coating in an        amount ranging between about 10% to about 25% by weight.

5685. The device of item 5641, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

5686. The device of item 5641, further comprising a coating, wherein thecoating further comprises a polymer.

5687. The device of item 5641, further comprising a first coating havinga first composition and the second coating having a second composition.

5688. The device of item 5641, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

5689. The device of item 5641, further comprising a polymer.

5690. The device of item 5641, further comprising a polymeric carrier.

5691. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

5692. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

5693. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

5694. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

5695. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

5696. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

5697. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

5698. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

5699. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

5700. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

5701. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

5702. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

5703. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

5704. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

5705. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

5706. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

5707. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

5708. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

5709. The device of item 5641, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

5710. The device of item 5641, further comprising a lubricious coating.

5711. The device of item 5641 wherein the fibrosing agent is locatedwithin pores or holes of the device.

5712. The device of item 5641 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

5713. The device of item 5641, further comprising a secondpharmaceutically active agent.

5714. The device of item 5641, further comprising an anti-inflammatoryagent.

5715. The device of item 5641, further comprising an agent that inhibitsinfection.

5716. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

5717. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

5718. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

5719. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

5720. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

5721. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

5722. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

5723. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

5724. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

5725. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

5726. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

5727. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

5728. The device of item 5641, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

5729. The device of item 5641, further comprising an anti-thromboticagent.

5730. The device of item 5641, further comprising a visualization agent.

5731. The device of item 5641, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

5732. The device of item 5641, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

5733. The device of item 5641, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

5734. The device of item 5641, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

5735. The device of item 5641, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

5736. The device of item 5641, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

5737. The device of item 5641, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

5738. The device of item 5641, further comprising an echogenic material.

5739. The device of item 5641, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

5740. The device of item 5641 wherein the device is sterile.

5741. The device of item 5641 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

5742. The device of item 5641 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

5743. The device of item 5641 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

5744. The device of item 5641 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

5745. The device of item 5641 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

5746. The device of item 5641 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

5747. The device of item 5641 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

5748. The device of item 5641 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

5749. The device of item 5641 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

5750. The device of item 5641 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

5751. The device of item 5641 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

5752. The device of item 5641 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

5753. The device of item 5641 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

5754. The device of item 5641 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

5755. The device of item 5641 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

5756. The device of item 5641 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

5757. The device of item 5641 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

5758. The device of item 5641 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

5759. The device of item 5641 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

5760. The device of item 5641 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5761. The device of item 5641 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5762. The device of item 5641 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5763. The device of item 5641 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

5764. The device of item 5641 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5765. The device of item 5641 wherein the Vas Deferens implant isinjectable.

5766. The device of item 5641 wherein the Vas Deferens implant is avasectomy suture.

5767. The device of item 5641 wherein the Vas Deferens implant is avasectomy clip.

5768. A medical device comprising a gastric restriction implant and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

5769. The device of item 5768 wherein the fibrosing agent promotesregeneration.

5770. The device of item 5768 wherein the fibrosing agent promotesangiogenesis.

5771. The device of item 5768 wherein the fibrosing agent promotesfibroblast migration.

5772. The device of item 5768 wherein the fibrosing agent promotesfibroblast proliferation.

5773. The device of item 5768 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

5774. The device of item 5768 wherein the fibrosing agent promotestissue remodeling.

5775. The device of item 5768 wherein the fibrosing agent is an arterialvessel wall irritant.

5776. The device of item 5768 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5777. The device of item 5768 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5778. The device of item 5768 wherein the fibrosing agent is orcomprises silk.

5779. The device of item 5768 wherein the fibrosing agent is orcomprises mineral particles.

5780. The device of item 5768 wherein the fibrosing agent is orcomprises chitosan.

5781. The device of item 5768 wherein the fibrosing agent is orcomprises polylysine.

5782. The device of item 5768 wherein the fibrosing agent is orcomprises fibronectin.

5783. The device of item 5768 wherein the fibrosing agent is orcomprises bleomycin.

5784. The device of item 5768 wherein the fibrosing agent is orcomprises CTGF.

5785. The device of item 5768 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

5786. The device of item 5768 wherein the fibrosing agent is in the formof a particulate.

5787. The device of item 5768 wherein the composition further comprisesan inflammatory cytokine.

5788. The device of item 5768 wherein the composition further comprisesan agent that stimulates cell proliferation.

5789. The device of item 5768 wherein the composition is in the form ofa gel, paste, or spray.

5790. The device of item 5768 wherein the fibrosing agent is in the formof tufts.

5791. The device of item 5768, further comprising a polymer.

5792. The device of item 5768, further comprising a polymeric carrier.

5793. The device of item 5768 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5794. The device of item 5768 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5795. The device of item 5768, further comprising a coating, wherein thecoating comprises the fibrosing agent.

5796. The device of item 5768, further comprising a coating, wherein thecoating is disposed on a surface of the device.

5797. The device of item 5768, further comprising a coating, wherein thecoating directly contacts the device.

5798. The device of item 5768, further comprising a coating, wherein thecoating indirectly contacts the device.

5799. The device of item 5768, further comprising a coating, wherein thecoating partially covers the device.

5800. The device of item 5768, further comprising a coating, wherein thecoating completely covers the device.

5801. The device of item 5768, further comprising a coating, wherein thecoating is a uniform coating.

5802. The device of item 5768, further comprising a coating, wherein thecoating is a non-uniform coating.

5803. The device of item 5768, further comprising a coating, wherein thecoating is a discontinuous coating.

5804. The device of item 5768, further comprising a coating, wherein thecoating is a patterned coating.

5805. The device of item 5768, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

5806. The device of item 5768, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

5807. The device of item 5768, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

5808. The device of item 5768, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

5809. The device of item 5768, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

5810. The device of item 5768, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

5811. The device of item 5768, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

5812. The device of item 5768, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

5813. The device of item 5768, further comprising a coating, wherein thecoating further comprises a polymer.

5814. The device of item 5768, further comprising a first coating havinga first composition and the second coating having a second composition.

5815. The device of item 5768, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

5816. The device of item 5768, further comprising a polymer.

5817. The device of item 5768, further comprising a polymeric carrier.

5818. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

5819. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

5820. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

5821. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

5822. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

5823. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

5824. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

5825. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

5826. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

5827. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

5828. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

5829. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

5830. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

5831. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

5832. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

5833. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

5834. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

5835. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

5836. The device of item 5768, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

5837. The device of item 5768, further comprising a lubricious coating.

5838. The device of item 5768 wherein the fibrosing agent is locatedwithin pores or holes of the device.

5839. The device of item 5768 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

5840. The device of item 5768, further comprising a secondpharmaceutically active agent.

5841. The device of item 5768, further comprising an anti-inflammatoryagent.

5842. The device of item 5768, further comprising an agent that inhibitsinfection.

5843. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

5844. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

5845. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

5846. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

5847. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

5848. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

5849. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

5850. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

5851. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

5852. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

5853. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

5854. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

5855. The device of item 5768, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

5856. The device of item 5768, further comprising an anti-thromboticagent.

5857. The device of item 5768, further comprising a visualization agent.

5858. The device of item 5768, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

5859. The device of item 5768, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

5860. The device of item 5768, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

5861. The device of item 5768, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

5862. The device of item 5768, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

5863. The device of item 5768, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

5864. The device of item 5768, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

5865. The device of item 5768, further comprising an echogenic material.

5866. The device of item 5768, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

5867. The device of item 5768 wherein the device is sterile.

5868. The device of item 5768 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

5869. The device of item 5768 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

5870. The device of item 5768 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

5871. The device of item 5768 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

5872. The device of item 5768 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

5873. The device of item 5768 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

5874. The device of item 5768 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

5875. The device of item 5768 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

5876. The device of item 5768 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

5877. The device of item 5768 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

5878. The device of item 5768 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

5879. The device of item 5768 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

5880. The device of item 5768 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

5881. The device of item 5768 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

5882. The device of item 5768 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

5883. The device of item 5768 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

5884. The device of item 5768 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

5885. The device of item 5768 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

5886. The device of item 5768 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

5887. The device of item 5768 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5888. The device of item 5768 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5889. The device of item 5768 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5890. The device of item 5768 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

5891. The device of item 5768 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

5892. The device of item 5768 wherein the gastric restriction implant isan inflatable cuff.

5893. The device of item 5768 wherein the gastric restriction implant isa space occuping device.

5894. A medical device comprising a suture-based endoluminal implant forpartitioning the stomach, and a fibrosing agent, where the fibrosingagent induces a fibrotic response between the device and a patient inwhich the device is implanted.

5895. The device of item 5894 wherein the fibrosing agent promotesregeneration.

5896. The device of item 5894 wherein the fibrosing agent promotesangiogenesis.

5897. The device of item 5894 wherein the fibrosing agent promotesfibroblast migration.

5898. The device of item 5894 wherein the fibrosing agent promotesfibroblast proliferation.

5899. The device of item 5894 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

5900. The device of item 5894 wherein the fibrosing agent promotestissue remodeling.

5901. The device of item 5894 wherein the fibrosing agent is an arterialvessel wall irritant.

5902. The device of item 5894 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5903. The device of item 5894 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5904. The device of item 5894 wherein the fibrosing agent is orcomprises silk.

5905. The device of item 5894 wherein the fibrosing agent is orcomprises mineral particles.

5906. The device of item 5894 wherein the fibrosing agent is orcomprises chitosan.

5907. The device of item 5894 wherein the fibrosing agent is orcomprises polylysine.

5908. The device of item 5894 wherein the fibrosing agent is orcomprises fibronectin.

5909. The device of item 5894 wherein the fibrosing agent is orcomprises bleomycin.

5910. The device of item 5894 wherein the fibrosing agent is orcomprises CTGF.

5911. The device of item 5894 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

5912. The device of item 5894 wherein the fibrosing agent is in the formof a particulate.

5913. The device of item 5894 wherein the composition further comprisesan inflammatory cytokine.

5914. The device of item 5894 wherein the composition further comprisesan agent that stimulates cell proliferation.

5915. The device of item 5894 wherein the composition is in the form ofa gel, paste, or spray.

5916. The device of item 5894 wherein the fibrosing agent is in the formof tufts.

5917. The device of item 5894, further comprising a polymer.

5918. The device of item 5894, further comprising a polymeric carrier.

5919. The device of item 5894 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

5920. The device of item 5894 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

5921. The device of item 5894, further comprising a coating, wherein thecoating comprises the fibrosing agent.

5922. The device of item 5894, further comprising a coating, wherein thecoating is disposed on a surface of the device.

5923. The device of item 5894, further comprising a coating, wherein thecoating directly contacts the device.

5924. The device of item 5894, further comprising a coating, wherein thecoating indirectly contacts the device.

5925. The device of item 5894, further comprising a coating, wherein thecoating partially covers the device.

5926. The device of item 5894, further comprising a coating, wherein thecoating completely covers the device.

5927. The device of item 5894, further comprising a coating, wherein thecoating is a uniform coating.

5928. The device of item 5894, further comprising a coating, wherein thecoating is a non-uniform coating.

5929. The device of item 5894, further comprising a coating, wherein thecoating is a discontinuous coating.

5930. The device of item 5894, further comprising a coating, wherein thecoating is a patterned coating.

5931. The device of item 5894, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

5932. The device of item 5894, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

5933. The device of item 5894, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

5934. The device of item 5894, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

5935. The device of item 5894, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

5936. The device of item 5894, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

5937. The device of item 5894, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

5938. The device of item 5894, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

5939. The device of item 5894, further comprising a coating, wherein thecoating further comprises a polymer.

5940. The device of item 5894, further comprising a first coating havinga first composition and the second coating having a second composition.

5941. The device of item 5894, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

5942. The device of item 5894, further comprising a polymer.

5943. The device of item 5894, further comprising a polymeric carrier.

5944. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

5945. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

5946. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

5947. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

5948. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

5949. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

5950. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

5951. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

5952. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

5953. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

5954. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

5955. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

5956. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

5957. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

5958. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

5959. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

5960. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

5961. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

5962. The device of item 5894, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

5963. The device of item 5894, further comprising a lubricious coating.

5964. The device of item 5894 wherein the fibrosing agent is locatedwithin pores or holes of the device.

5965. The device of item 5894 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

5966. The device of item 5894, further comprising a secondpharmaceutically active agent.

5967. The device of item 5894, further comprising an anti-inflammatoryagent.

5968. The device of item 5894, further comprising an agent that inhibitsinfection.

5969. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

5970. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

5971. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

5972. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

5973. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

5974. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

5975. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

5976. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

5977. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

5978. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

5979. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

5980. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

5981. The device of item 5894, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

5982. The device of item 5894, further comprising an anti-thromboticagent.

5983. The device of item 5894, further comprising a visualization agent.

5984. The device of item 5894, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

5985. The device of item 5894, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

5986. The device of item 5894, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

5987. The device of item 5894, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

5988. The device of item 5894, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

5989. The device of item 5894, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

5990. The device of item 5894, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

5991. The device of item 5894, further comprising an echogenic material.

5992. The device of item 5894, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

5993. The device of item 5894 wherein the device is sterile.

5994. The device of item 5894 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

5995. The device of item 5894 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

5996. The device of item 5894 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

5997. The device of item 5894 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

5998. The device of item 5894 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

5999. The device of item 5894 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

6000. The device of item 5894 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

6001. The device of item 5894 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

6002. The device of item 5894 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

6003. The device of item 5894 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

6004. The device of item 5894 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

6005. The device of item 5894 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

6006. The device of item 5894 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

6007. The device of item 5894 wherein the device comprises about 0.01 gto about 10 μg of the fibrosing agent.

6008. The device of item 5894 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

6009. The device of item 5894 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

6010. The device of item 5894 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

6011. The device of item 5894 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

6012. The device of item 5894 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

6013. The device of item 5894 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6014. The device of item 5894 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6015. The device of item 5894 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6016. The device of item 5894 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

6017. The device of item 5894 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6018. A medical device comprising an electrostimulation implant and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

6019. The device of item 6018 wherein the fibrosing agent promotesregeneration.

6020. The device of item 6018 wherein the fibrosing agent promotesangiogenesis.

6021. The device of item 6018 wherein the fibrosing agent promotesfibroblast migration.

6022. The device of item 6018 wherein the fibrosing agent promotesfibroblast proliferation.

6023. The device of item 6018 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

6024. The device of item 6018 wherein the fibrosing agent promotestissue remodeling.

6025. The device of item 6018 wherein the fibrosing agent is an arterialvessel wall irritant.

6026. The device of item 6018 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6027. The device of item 6018 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6028. The device of item 6018 wherein the fibrosing agent is orcomprises silk.

6029. The device of item 6018 wherein the fibrosing agent is orcomprises mineral particles.

6030. The device of item 6018 wherein the fibrosing agent is orcomprises chitosan.

6031. The device of item 6018 wherein the fibrosing agent is orcomprises polylysine.

6032. The device of item 6018 wherein the fibrosing agent is orcomprises fibronectin.

6033. The device of item 6018 wherein the fibrosing agent is orcomprises bleomycin.

6034. The device of item 6018 wherein the fibrosing agent is orcomprises CTGF.

6035. The device of item 6018 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

6036. The device of item 6018 wherein the fibrosing agent is in the formof a particulate.

6037. The device of item 6018 wherein the composition further comprisesan inflammatory cytokine.

6038. The device of item 6018 wherein the composition further comprisesan agent that stimulates cell proliferation.

6039. The device of item 6018 wherein the composition is in the form ofa gel, paste, or spray.

6040. The device of item 6018 wherein the fibrosing agent is in the formof tufts.

6041. The device of item 6018, further comprising a polymer.

6042. The device of item 6018, further comprising a polymeric carrier.

6043. The device of item 6018 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6044. The device of item 6018 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6045. The device of item 6018, further comprising a coating, wherein thecoating comprises the fibrosing agent.

6046. The device of item 6018, further comprising a coating, wherein thecoating is disposed on a surface of the device.

6047. The device of item 6018, further comprising a coating, wherein thecoating directly contacts the device.

6048. The device of item 6018, further comprising a coating, wherein thecoating indirectly contacts the device.

6049. The device of item 6018, further comprising a coating, wherein thecoating partially covers the device.

6050. The device of item 6018, further comprising a coating, wherein thecoating completely covers the device.

6051. The device of item 6018, further comprising a coating, wherein thecoating is a uniform coating.

6052. The device of item 6018, further comprising a coating, wherein thecoating is a non-uniform coating.

6053. The device of item 6018, further comprising a coating, wherein thecoating is a discontinuous coating.

6054. The device of item 6018, further comprising a coating, wherein thecoating is a patterned coating.

6055. The device of item 6018, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

6056. The device of item 6018, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

6057. The device of item 6018, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

6058. The device of item 6018, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

6059. The device of item 6018, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

6060. The device of item 6018, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

6061. The device of item 6018, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

6062. The device of item 6018, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

6063. The device of item 6018, further comprising a coating, wherein thecoating further comprises a polymer.

6064. The device of item 6018, further comprising a first coating havinga first composition and the second coating having a second composition.

6065. The device of item 6018, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

6066. The device of item 6018, further comprising a polymer.

6067. The device of item 6018, further comprising a polymeric carrier.

6068. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

6069. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

6070. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

6071. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

6072. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

6073. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

6074. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

6075. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

6076. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

6077. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

6078. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

6079. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

6080. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

6081. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

6082. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

6083. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

6084. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

6085. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

6086. The device of item 6018, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

6087. The device of item 6018, further comprising a lubricious coating.

6088. The device of item 6018 wherein the fibrosing agent is locatedwithin pores or holes of the device.

6089. The device of item 6018 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

6090. The device of item 6018, further comprising a secondpharmaceutically active agent.

6091. The device of item 6018, further comprising an anti-inflammatoryagent.

6092. The device of item 6018, further comprising an agent that inhibitsinfection.

6093. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

6094. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

6095. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

6096. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

6097. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

6098. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

6099. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

6100. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

6101. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

6102. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

6103. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

6104. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

6105. The device of item 6018, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

6106. The device of item 6018, further comprising an anti-thromboticagent.

6107. The device of item 6018, further comprising a visualization agent.

6108. The device of item 6018, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

6109. The device of item 6018, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

6110. The device of item 6018, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

6111. The device of item 6018, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

6112. The device of item 6018, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

6113. The device of item 6018, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

6114. The device of item 6018, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

6115. The device of item 6018, further comprising an echogenic material.

6116. The device of item 6018, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

6117. The device of item 6018 wherein the device is sterile.

6118. The device of item 6018 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

6119. The device of item 6018 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

6120. The device of item 6018 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

6121. The device of item 6018 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

6122. The device of item 6018 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

6123. The device of item 6018 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

6124. The device of item 6018 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

6125. The device of item 6018 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

6126. The device of item 6018 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

6127. The device of item 6018 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

6128. The device of item 6018 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

6129. The device of item 6018 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

6130. The device of item 6018 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

6131. The device of item 6018 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

6132. The device of item 6018 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

6133. The device of item 6018 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

6134. The device of item 6018 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

6135. The device of item 6018 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

6136. The device of item 6018 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

6137. The device of item 6018 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6138. The device of item 6018 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6139. The device of item 6018 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6140. The device of item 6018 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

6141. The device of item 6018 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6142. The device of item 6018 wherein the electostimulation implant is aneural electostimulation implant.

6143. The device of item 6018 wherein the electostimulation implant is anon-neural electostimulation implant.

6144. A medical device comprising a soft palate implant and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

6145. The device of item 6144 wherein the fibrosing agent promotesregeneration.

6146. The device of item 6144 wherein the fibrosing agent promotesangiogenesis.

6147. The device of item 6144 wherein the fibrosing agent promotesfibroblast migration.

6148. The device of item 6144 wherein the fibrosing agent promotesfibroblast proliferation.

6149. The device of item 6144 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

6150. The device of item 6144 wherein the fibrosing agent promotestissue remodeling.

6151. The device of item 6144 wherein the fibrosing agent is an arterialvessel wall irritant.

6152. The device of item 6144 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6153. The device of item 6144 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6154. The device of item 6144 wherein the fibrosing agent is orcomprises silk.

6155. The device of item 6144 wherein the fibrosing agent is orcomprises mineral particles.

6156. The device of item 6144 wherein the fibrosing agent is orcomprises chitosan.

6157. The device of item 6144 wherein the fibrosing agent is orcomprises polylysine.

6158. The device of item 6144 wherein the fibrosing agent is orcomprises fibronectin.

6159. The device of item 6144 wherein the fibrosing agent is orcomprises bleomycin.

6160. The device of item 6144 wherein the fibrosing agent is orcomprises CTGF.

6161. The device of item 6144 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

6162. The device of item 6144 wherein the fibrosing agent is in the formof a particulate.

6163. The device of item 6144 wherein the composition further comprisesan inflammatory cytokine.

6164. The device of item 6144 wherein the composition further comprisesan agent that stimulates cell proliferation.

6165. The device of item 6144 wherein the composition is in the form ofa gel, paste, or spray.

6166. The device of item 6144 wherein the fibrosing agent is in the formof tufts.

6167. The device of item 6144, further comprising a polymer.

6168. The device of item 6144, further comprising a polymeric carrier.

6169. The device of item 6144 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6170. The device of item 6144 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6171. The device of item 6144, further comprising a coating, wherein thecoating comprises the fibrosing agent.

6172. The device of item 6144, further comprising a coating, wherein thecoating is disposed on a surface of the device.

6173. The device of item 6144, further comprising a coating, wherein thecoating directly contacts the device.

6174. The device of item 6144, further comprising a coating, wherein thecoating indirectly contacts the device.

6175. The device of item 6144, further comprising a coating, wherein thecoating partially covers the device.

6176. The device of item 6144, further comprising a coating, wherein thecoating completely covers the device.

6177. The device of item 6144, further comprising a coating, wherein thecoating is a uniform coating.

6178. The device of item 6144, further comprising a coating, wherein thecoating is a non-uniform coating.

6179. The device of item 6144, further comprising a coating, wherein thecoating is a discontinuous coating.

6180. The device of item 6144, further comprising a coating, wherein thecoating is a patterned coating.

6181. The device of item 6144, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

6182. The device of item 6144, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

6183. The device of item 6144, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

6184. The device of item 6144, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

6185. The device of item 6144, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

6186. The device of item 6144, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

6187. The device of item 6144, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

6188. The device of item 6144, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

6189. The device of item 6144, further comprising a coating, wherein thecoating further comprises a polymer.

6190. The device of item 6144, further comprising a first coating havinga first composition and the second coating having a second composition.

6191. The device of item 6144, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

6192. The device of item 6144, further comprising a polymer.

6193. The device of item 6144, further comprising a polymeric carrier.

6194. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

6195. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

6196. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

6197. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

6198. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

6199. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

6200. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

6201. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

6202. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

6203. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

6204. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

6205. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

6206. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

6207. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

6208. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

6209. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

6210. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

6211. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

6212. The device of item 6144, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

6213. The device of item 6144, further comprising a lubricious coating.

6214. The device of item 6144 wherein the fibrosing agent is locatedwithin pores or holes of the device.

6215. The device of item 6144 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

6216. The device of item 6144, further comprising a secondpharmaceutically active agent.

6217. The device of item 6144, further comprising an anti-inflammatoryagent.

6218. The device of item 6144, further comprising an agent that inhibitsinfection.

6219. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

6220. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

6221. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

6222. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

6223. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

6224. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

6225. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

6226. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

6227. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

6228. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

6229. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

6230. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

6231. The device of item 6144, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

6232. The device of item 6144, further comprising an anti-thromboticagent.

6233. The device of item 6144, further comprising a visualization agent.

6234. The device of item 6144, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

6235. The device of item 6144, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

6236. The device of item 6144, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

6237. The device of item 6144, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

6238. The device of item 6144, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

6239. The device of item 6144, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

6240. The device of item 6144, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

6241. The device of item 6144, further comprising an echogenic material.

6242. The device of item 6144, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

6243. The device of item 6144 wherein the device is sterile.

6244. The device of item 6144 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

6245. The device of item 6144 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

6246. The device of item 6144 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

6247. The device of item 6144 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

6248. The device of item 6144 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

6249. The device of item 6144 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

6250. The device of item 6144 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

6251. The device of item 6144 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

6252. The device of item 6144 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

6253. The device of item 6144 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

6254. The device of item 6144 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

6255. The device of item 6144 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

6256. The device of item 6144 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

6257. The device of item 6144 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

6258. The device of item 6144 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

6259. The device of item 6144 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

6260. The device of item 6144 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

6261. The device of item 6144 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

6262. The device of item 6144 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

6263. The device of item 6144 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6264. The device of item 6144 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6265. The device of item 6144 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6266. The device of item 6144 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

6267. The device of item 6144 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6268. The device of item 6144 wherein the soft palate implant isinjectable.

6269. A medical device comprising a vascular coil implant and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

6270. The device of item 6269 wherein the fibrosing agent promotesregeneration.

6271. The device of item 6269 wherein the fibrosing agent promotesangiogenesis.

6272. The device of item 6269 wherein the fibrosing agent promotesfibroblast migration.

6273. The device of item 6269 wherein the fibrosing agent promotesfibroblast proliferation.

6274. The device of item 6269 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

6275. The device of item 6269 wherein the fibrosing agent promotestissue remodeling.

6276. The device of item 6269 wherein the fibrosing agent is an arterialvessel wall irritant.

6277. The device of item 6269 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6278. The device of item 6269 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6279. The device of item 6269 wherein the fibrosing agent is orcomprises silk.

6280. The device of item 6269 wherein the fibrosing agent is orcomprises mineral particles.

6281. The device of item 6269 wherein the fibrosing agent is orcomprises chitosan.

6282. The device of item 6269 wherein the fibrosing agent is orcomprises polylysine.

6283. The device of item 6269 wherein the fibrosing agent is orcomprises fibronectin.

6284. The device of item 6269 wherein the fibrosing agent is orcomprises bleomycin.

6285. The device of item 6269 wherein the fibrosing agent is orcomprises CTGF.

6286. The device of item 6269 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

6287. The device of item 6269 wherein the fibrosing agent is in the formof a particulate.

6288. The device of item 6269 wherein the composition further comprisesan inflammatory cytokine.

6289. The device of item 6269 wherein the composition further comprisesan agent that stimulates cell proliferation.

6290. The device of item 6269 wherein the composition is in the form ofa gel, paste, or spray.

6291. The device of item 6269 wherein the fibrosing agent is in the formof tufts.

6292. The device of item 6269, further comprising a polymer.

6293. The device of item 6269, further comprising a polymeric carrier.

6294. The device of item 6269 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6295. The device of item 6269 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6296. The device of item 6269, further comprising a coating, wherein thecoating comprises the fibrosing agent.

6297. The device of item 6269, further comprising a coating, wherein thecoating is disposed on a surface of the device.

6298. The device of item 6269, further comprising a coating, wherein thecoating directly contacts the device.

6299. The device of item 6269, further comprising a coating, wherein thecoating indirectly contacts the device.

6300. The device of item 6269, further comprising a coating, wherein thecoating partially covers the device.

6301. The device of item 6269, further comprising a coating, wherein thecoating completely covers the device.

6302. The device of item 6269, further comprising a coating, wherein thecoating is a uniform coating.

6303. The device of item 6269, further comprising a coating, wherein thecoating is a non-uniform coating.

6304. The device of item 6269, further comprising a coating, wherein thecoating is a discontinuous coating.

6305. The device of item 6269, further comprising a coating, wherein thecoating is a patterned coating.

6306. The device of item 6269, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

6307. The device of item 6269, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

6308. The device of item 6269, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

6309. The device of item 6269, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

6310. The device of item 6269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

6311. The device of item 6269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

6312. The device of item 6269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

6313. The device of item 6269, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

6314. The device of item 6269, further comprising a coating, wherein thecoating further comprises a polymer.

6315. The device of item 6269, further comprising a first coating havinga first composition and the second coating having a second composition.

6316. The device of item 6269, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

6317. The device of item 6269, further comprising a polymer.

6318. The device of item 6269, further comprising a polymeric carrier.

6319. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

6320. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

6321. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

6322. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

6323. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

6324. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

6325. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

6326. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

6327. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

6328. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

6329. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

6330. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

6331. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

6332. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

6333. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

6334. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

6335. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

6336. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

6337. The device of item 6269, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

6338. The device of item 6269, further comprising a lubricious coating.

6339. The device of item 6269 wherein the fibrosing agent is locatedwithin pores or holes of the device.

6340. The device of item 6269 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

6341. The device of item 6269, further comprising a secondpharmaceutically active agent.

6342. The device of item 6269, further comprising an anti-inflammatoryagent.

6343. The device of item 6269, further comprising an agent that inhibitsinfection.

6344. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

6345. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

6346. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

6347. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

6348. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

6349. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

6350. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

6351. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

6352. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

6353. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

6354. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

6355. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

6356. The device of item 6269, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

6357. The device of item 6269, further comprising an anti-thromboticagent.

6358. The device of item 6269, further comprising a visualization agent.

6359. The device of item 6269, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

6360. The device of item 6269, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

6361. The device of item 6269, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

6362. The device of item 6269, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

6363. The device of item 6269, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

6364. The device of item 6269, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

6365. The device of item 6269, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

6366. The device of item 6269, further comprising an echogenic material.

6367. The device of item 6269, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

6368. The device of item 6269 wherein the device is sterile.

6369. The device of item 6269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

6370. The device of item 6269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

6371. The device of item 6269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

6372. The device of item 6269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

6373. The device of item 6269 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

6374. The device of item 6269 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

6375. The device of item 6269 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

6376. The device of item 6269 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

6377. The device of item 6269 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

6378. The device of item 6269 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

6379. The device of item 6269 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

6380. The device of item 6269 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

6381. The device of item 6269 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

6382. The device of item 6269 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

6383. The device of item 6269 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

6384. The device of item 6269 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

6385. The device of item 6269 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

6386. The device of item 6269 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

6387. The device of item 6269 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

6388. The device of item 6269 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6389. The device of item 6269 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6390. The device of item 6269 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6391. The device of item 6269 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

6392. The device of item 6269 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6393. The device of item 6269 wherein the vascular coil implant iscomposed of a porous, flexible PTFE material.

6394. The device of item 6269 wherein the vascular coil implant iscomposed of a bioactive component.

6395. The device of item 6269 wherein the vascular coil implant isbiologically inert.

6396. The device of item 6269 wherein the vascular coil implant have afirst state prior to insertion (primary phase) and a second state postinsertion (secondary phase).

6397. A medical device comprising a vaso-occlusive coil implant and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

6398. The device of item 6397 wherein the fibrosing agent promotesregeneration.

6399. The device of item 6397 wherein the fibrosing agent promotesangiogenesis.

6400. The device of item 6397 wherein the fibrosing agent promotesfibroblast migration.

6401. The device of item 6397 wherein the fibrosing agent promotesfibroblast proliferation.

6402. The device of item 6397 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

6403. The device of item 6397 wherein the fibrosing agent promotestissue remodeling.

6404. The device of item 6397 wherein the fibrosing agent is an arterialvessel wall irritant.

6405. The device of item 6397 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6406. The device of item 6397 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6407. The device of item 6397 wherein the fibrosing agent is orcomprises silk.

6408. The device of item 6397 wherein the fibrosing agent is orcomprises mineral particles.

6409. The device of item 6397 wherein the fibrosing agent is orcomprises chitosan.

6410. The device of item 6397 wherein the fibrosing agent is orcomprises polylysine.

6411. The device of item 6397 wherein the fibrosing agent is orcomprises fibronectin.

6412. The device of item 6397 wherein the fibrosing agent is orcomprises bleomycin.

6413. The device of item 6397 wherein the fibrosing agent is orcomprises CTGF.

6414. The device of item 6397 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

6415. The device of item 6397 wherein the fibrosing agent is in the formof a particulate.

6416. The device of item 6397 wherein the composition further comprisesan inflammatory cytokine.

6417. The device of item 6397 wherein the composition further comprisesan agent that stimulates cell proliferation.

6418. The device of item 6397 wherein the composition is in the form ofa gel, paste, or spray.

6419. The device of item 6397 wherein the fibrosing agent is in the formof tufts.

6420. The device of item 6397, further comprising a polymer.

6421. The device of item 6397, further comprising a polymeric carrier.

6422. The device of item 6397 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6423. The device of item 6397 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6424. The device of item 6397, further comprising a coating, wherein thecoating comprises the fibrosing agent.

6425. The device of item 6397, further comprising a coating, wherein thecoating is disposed on a surface of the device.

6426. The device of item 6397, further comprising a coating, wherein thecoating directly contacts the device.

6427. The device of item 6397, further comprising a coating, wherein thecoating indirectly contacts the device.

6428. The device of item 6397, further comprising a coating, wherein thecoating partially covers the device.

6429. The device of item 6397, further comprising a coating, wherein thecoating completely covers the device.

6430. The device of item 6397, further comprising a coating, wherein thecoating is a uniform coating.

6431. The device of item 6397, further comprising a coating, wherein thecoating is a non-uniform coating.

6432. The device of item 6397, further comprising a coating, wherein thecoating is a discontinuous coating.

6433. The device of item 6397, further comprising a coating, wherein thecoating is a patterned coating.

6434. The device of item 6397, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

6435. The device of item 6397, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

6436. The device of item 6397, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

6437. The device of item 6397, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

6438. The device of item 6397, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

6439. The device of item 6397, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

6440. The device of item 6397, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

6441. The device of item 6397, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

6442. The device of item 6397, further comprising a coating, wherein thecoating further comprises a polymer.

6443. The device of item 6397, further comprising a first coating havinga first composition and the second coating having a second composition.

6444. The device of item 6397, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

6445. The device of item 6397, further comprising a polymer.

6446. The device of item 6397, further comprising a polymeric carrier.

6447. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

6448. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

6449. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

6450. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

6451. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

6452. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

6453. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

6454. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

6455. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

6456. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

6457. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

6458. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

6459. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

6460. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

6461. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

6462. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

6463. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

6464. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

6465. The device of item 6397, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

6466. The device of item 6397, further comprising a lubricious coating.

6467. The device of item 6397 wherein the fibrosing agent is locatedwithin pores or holes of the device.

6468. The device of item 6397 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

6469. The device of item 6397, further comprising a secondpharmaceutically active agent.

6470. The device of item 6397, further comprising an anti-inflammatoryagent.

6471. The device of item 6397, further comprising an agent that inhibitsinfection.

6472. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

6473. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

6474. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

6475. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

6476. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

6477. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

6478. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

6479. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

6480. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

6481. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

6482. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

6483. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

6484. The device of item 6397, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

6485. The device of item 6397, further comprising an anti-thromboticagent.

6486. The device of item 6397, further comprising a visualization agent.

6487. The device of item 6397, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

6488. The device of item 6397, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

6489. The device of item 6397, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

6490. The device of item 6397, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

6491. The device of item 6397, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

6492. The device of item 6397, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

6493. The device of item 6397, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

6494. The device of item 6397, further comprising an echogenic material.

6495. The device of item 6397, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

6496. The device of item 6397 wherein the device is sterile.

6497. The device of item 6397 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

6498. The device of item 6397 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

6499. The device of item 6397 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

6500. The device of item 6397 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

6501. The device of item 6397 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

6502. The device of item 6397 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

6503. The device of item 6397 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

6504. The device of item 6397 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

6505. The device of item 6397 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

6506. The device of item 6397 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

6507. The device of item 6397 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

6508. The device of item 6397 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

6509. The device of item 6397 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

6510. The device of item 6397 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

6511. The device of item 6397 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

6512. The device of item 6397 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

6513. The device of item 6397 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

6514. The device of item 6397 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

6515. The device of item 6397 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

6516. The device of item 6397 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6517. The device of item 6397 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6518. The device of item 6397 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6519. The device of item 6397 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

6520. The device of item 6397 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6521. A medical device comprising a vaso-occlusion implant and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

6522. The device of item 6521 wherein the fibrosing agent promotesregeneration.

6523. The device of item 6521 wherein the fibrosing agent promotesangiogenesis.

6524. The device of item 6521 wherein the fibrosing agent promotesfibroblast migration.

6525. The device of item 6521 wherein the fibrosing agent promotesfibroblast proliferation.

6526. The device of item 6521 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

6527. The device of item 6521 wherein the fibrosing agent promotestissue remodeling.

6528. The device of item 6521 wherein the fibrosing agent is an arterialvessel wall irritant.

6529. The device of item 6521 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6530. The device of item 6521 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6531. The device of item 6521 wherein the fibrosing agent is orcomprises silk.

6532. The device of item 6521 wherein the fibrosing agent is orcomprises mineral particles.

6533. The device of item 6521 wherein the fibrosing agent is orcomprises chitosan.

6534. The device of item 6521 wherein the fibrosing agent is orcomprises polylysine.

6535. The device of item 6521 wherein the fibrosing agent is orcomprises fibronectin.

6536. The device of item 6521 wherein the fibrosing agent is orcomprises bleomycin.

6537. The device of item 6521 wherein the fibrosing agent is orcomprises CTGF.

6538. The device of item 6521 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

6539. The device of item 6521 wherein the fibrosing agent is in the formof a particulate.

6540. The device of item 6521 wherein the composition further comprisesan inflammatory cytokine.

6541. The device of item 6521 wherein the composition further comprisesan agent that stimulates cell proliferation.

6542. The device of item 6521 wherein the composition is in the form ofa gel, paste, or spray.

6543. The device of item 6521 wherein the fibrosing agent is in the formof tufts.

6544. The device of item 6521, further comprising a polymer.

6545. The device of item 6521, further comprising a polymeric carrier.

6546. The device of item 6521 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6547. The device of item 6521 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6548. The device of item 6521, further comprising a coating, wherein thecoating comprises the fibrosing agent.

6549. The device of item 6521, further comprising a coating, wherein thecoating is disposed on a surface of the device.

6550. The device of item 6521, further comprising a coating, wherein thecoating directly contacts the device.

6551. The device of item 6521, further comprising a coating, wherein thecoating indirectly contacts the device.

6552. The device of item 6521, further comprising a coating, wherein thecoating partially covers the device.

6553. The device of item 6521, further comprising a coating, wherein thecoating completely covers the device.

6554. The device of item 6521, further comprising a coating, wherein thecoating is a uniform coating.

6555. The device of item 6521, further comprising a coating, wherein thecoating is a non-uniform coating.

6556. The device of item 6521, further comprising a coating, wherein thecoating is a discontinuous coating.

6557. The device of item 6521, further comprising a coating, wherein thecoating is a patterned coating.

6558. The device of item 6521, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

6559. The device of item 6521, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

6560. The device of item 6521, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

6561. The device of item 6521, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

6562. The device of item 6521, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

6563. The device of item 6521, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

6564. The device of item 6521, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

6565. The device of item 6521, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

6566. The device of item 6521, further comprising a coating, wherein thecoating further comprises a polymer.

6567. The device of item 6521, further comprising a first coating havinga first composition and the second coating having a second composition.

6568. The device of item 6521, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

6569. The device of item 6521, further comprising a polymer.

6570. The device of item 6521, further comprising a polymeric carrier.

6571. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

6572. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

6573. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

6574. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

6575. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

6576. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

6577. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

6578. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

6579. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

6580. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

6581. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

6582. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

6583. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

6584. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

6585. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

6586. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

6587. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

6588. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

6589. The device of item 6521, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

6590. The device of item 6521, further comprising a lubricious coating.

6591. The device of item 6521 wherein the fibrosing agent is locatedwithin pores or holes of the device.

6592. The device of item 6521 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

6593. The device of item 6521, further comprising a secondpharmaceutically active agent.

6594. The device of item 6521, further comprising an anti-inflammatoryagent.

6595. The device of item 6521, further comprising an agent that inhibitsinfection.

6596. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

6597. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

6598. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

6599. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

6600. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

6601. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

6602. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

6603. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

6604. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

6605. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

6606. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

6607. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

6608. The device of item 6521, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

6609. The device of item 6521, further comprising an anti-thromboticagent.

6610. The device of item 6521, further comprising a visualization agent.

6611. The device of item 6521, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

6612. The device of item 6521, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

6613. The device of item 6521, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

6614. The device of item 6521, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

6615. The device of item 6521, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

6616. The device of item 6521, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

6617. The device of item 6521, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

6618. The device of item 6521, further comprising an echogenic material.

6619. The device of item 6521, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

6620. The device of item 6521 wherein the device is sterile.

6621. The device of item 6521 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

6622. The device of item 6521 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

6623. The device of item 6521 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

6624. The device of item 6521 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

6625. The device of item 6521 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

6626. The device of item 6521 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

6627. The device of item 6521 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

6628. The device of item 6521 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

6629. The device of item 6521 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

6630. The device of item 6521 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

6631. The device of item 6521 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

6632. The device of item 6521 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

6633. The device of item 6521 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

6634. The device of item 6521 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

6635. The device of item 6521 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

6636. The device of item 6521 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

6637. The device of item 6521 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

6638. The device of item 6521 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

6639. The device of item 6521 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

6640. The device of item 6521 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6641. The device of item 6521 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6642. The device of item 6521 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6643. The device of item 6521 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

6644. The device of item 6521 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6645. A medical device comprising a non-coiled vaso-occlusive implantand a fibrosing agent, where the fibrosing agent induces a fibroticresponse between the device and a patient in which the device isimplanted.

6646. The device of item 6645 wherein the fibrosing agent promotesregeneration.

6647. The device of item 6645 wherein the fibrosing agent promotesangiogenesis.

6648. The device of item 6645 wherein the fibrosing agent promotesfibroblast migration.

6649. The device of item 6645 wherein the fibrosing agent promotesfibroblast proliferation.

6650. The device of item 6645 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

6651. The device of item 6645 wherein the fibrosing agent promotestissue remodeling.

6652. The device of item 6645 wherein the fibrosing agent is an arterialvessel wall irritant.

6653. The device of item 6645 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6654. The device of item 6645 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6655. The device of item 6645 wherein the fibrosing agent is orcomprises silk.

6656. The device of item 6645 wherein the fibrosing agent is orcomprises mineral particles.

6657. The device of item 6645 wherein the fibrosing agent is orcomprises chitosan.

6658. The device of item 6645 wherein the fibrosing agent is orcomprises polylysine.

6659. The device of item 6645 wherein the fibrosing agent is orcomprises fibronectin.

6660. The device of item 6645 wherein the fibrosing agent is orcomprises bleomycin.

6661. The device of item 6645 wherein the fibrosing agent is orcomprises CTGF.

6662. The device of item 6645 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

6663. The device of item 6645 wherein the fibrosing agent is in the formof a particulate.

6664. The device of item 6645 wherein the composition further comprisesan inflammatory cytokine.

6665. The device of item 6645 wherein the composition further comprisesan agent that stimulates cell proliferation.

6666. The device of item 6645 wherein the composition is in the form ofa gel, paste, or spray.

6667. The device of item 6645 wherein the fibrosing agent is in the formof tufts.

6668. The device of item 6645, further comprising a polymer.

6669. The device of item 6645, further comprising a polymeric carrier.

6670. The device of item 6645 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6671. The device of item 6645 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6672. The device of item 6645, further comprising a coating, wherein thecoating comprises the fibrosing agent.

6673. The device of item 6645, further comprising a coating, wherein thecoating is disposed on a surface of the device.

6674. The device of item 6645, further comprising a coating, wherein thecoating directly contacts the device.

6675. The device of item 6645, further comprising a coating, wherein thecoating indirectly contacts the device.

6676. The device of item 6645, further comprising a coating, wherein thecoating partially covers the device.

6677. The device of item 6645, further comprising a coating, wherein thecoating completely covers the device.

6678. The device of item 6645, further comprising a coating, wherein thecoating is a uniform coating.

6679. The device of item 6645, further comprising a coating, wherein thecoating is a non-uniform coating.

6680. The device of item 6645, further comprising a coating, wherein thecoating is a discontinuous coating.

6681. The device of item 6645, further comprising a coating, wherein thecoating is a patterned coating.

6682. The device of item 6645, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

6683. The device of item 6645, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

6684. The device of item 6645, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

6685. The device of item 6645, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

6686. The device of item 6645, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

6687. The device of item 6645, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

6688. The device of item 6645, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

6689. The device of item 6645, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

6690. The device of item 6645, further comprising a coating, wherein thecoating further comprises a polymer.

6691. The device of item 6645, further comprising a first coating havinga first composition and the second coating having a second composition.

6692. The device of item 6645, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

6693. The device of item 6645, further comprising a polymer.

6694. The device of item 6645, further comprising a polymeric carrier.

6695. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

6696. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

6697. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

6698. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

6699. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

6700. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

6701. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

6702. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

6703. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

6704. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

6705. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

6706. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

6707. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

6708. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

6709. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

6710. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

6711. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

6712. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

6713. The device of item 6645, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

6714. The device of item 6645, further comprising a lubricious coating.

6715. The device of item 6645 wherein the fibrosing agent is locatedwithin pores or holes of the device.

6716. The device of item 6645 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

6717. The device of item 6645, further comprising a secondpharmaceutically active agent.

6718. The device of item 6645, further comprising an anti-inflammatoryagent.

6719. The device of item 6645, further comprising an agent that inhibitsinfection.

6720. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

6721. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

6722. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

6723. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

6724. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

6725. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

6726. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

6727. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

6728. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

6729. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

6730. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

6731. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

6732. The device of item 6645, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

6733. The device of item 6645, further comprising an anti-thromboticagent.

6734. The device of item 6645, further comprising a visualization agent.

6735. The device of item 6645, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

6736. The device of item 6645, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

6737. The device of item 6645, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

6738. The device of item 6645, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

6739. The device of item 6645, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

6740. The device of item 6645, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

6741. The device of item 6645, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

6742. The device of item 6645, further comprising an echogenic material.

6743. The device of item 6645, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

6744. The device of item 6645 wherein the device is sterile.

6745. The device of item 6645 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

6746. The device of item 6645 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

6747. The device of item 6645 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

6748. The device of item 6645 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

6749. The device of item 6645 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

6750. The device of item 6645 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

6751. The device of item 6645 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

6752. The device of item 6645 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

6753. The device of item 6645 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

6754. The device of item 6645 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

6755. The device of item 6645 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

6756. The device of item 6645 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

6757. The device of item 6645 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

6758. The device of item 6645 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

6759. The device of item 6645 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

6760. The device of item 6645 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

6761. The device of item 6645 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

6762. The device of item 6645 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

6763. The device of item 6645 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

6764. The device of item 6645 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6765. The device of item 6645 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6766. The device of item 6645 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6767. The device of item 6645 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

6768. The device of item 6645 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6769. The device of item 6645 wherein the vascular occlusion implant isexpandable.

6770. A medical device comprising a hernia mesh implant and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

6771. The device of item 6770 wherein the fibrosing agent promotesregeneration.

6772. The device of item 6770 wherein the fibrosing agent promotesangiogenesis.

6773. The device of item 6770 wherein the fibrosing agent promotesfibroblast migration.

6774. The device of item 6770 wherein the fibrosing agent promotesfibroblast proliferation.

6775. The device of item 6770 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

6776. The device of item 6770 wherein the fibrosing agent promotestissue remodeling.

6777. The device of item 6770 wherein the fibrosing agent is an arterialvessel wall irritant.

6778. The device of item 6770 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6779. The device of item 6770 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6780. The device of item 6770 wherein the fibrosing agent is orcomprises silk.

6781. The device of item 6770 wherein the fibrosing agent is orcomprises mineral particles.

6782. The device of item 6770 wherein the fibrosing agent is orcomprises chitosan.

6783. The device of item 6770 wherein the fibrosing agent is orcomprises polylysine.

6784. The device of item 6770 wherein the fibrosing agent is orcomprises fibronectin.

6785. The device of item 6770 wherein the fibrosing agent is orcomprises bleomycin.

6786. The device of item 6770 wherein the fibrosing agent is orcomprises CTGF.

6787. The device of item 6770 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

6788. The device of item 6770 wherein the fibrosing agent is in the formof a particulate.

6789. The device of item 6770 wherein the composition further comprisesan inflammatory cytokine.

6790. The device of item 6770 wherein the composition further comprisesan agent that stimulates cell proliferation.

6791. The device of item 6770 wherein the composition is in the form ofa gel, paste, or spray.

6792. The device of item 6770 wherein the fibrosing agent is in the formof tufts.

6793. The device of item 6770, further comprising a polymer.

6794. The device of item 6770, further comprising a polymeric carrier.

6795. The device of item 6770 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6796. The device of item 6770 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6797. The device of item 6770, further comprising a coating, wherein thecoating comprises the fibrosing agent.

6798. The device of item 6770, further comprising a coating, wherein thecoating is disposed on a surface of the device.

6799. The device of item 6770, further comprising a coating, wherein thecoating directly contacts the device.

6800. The device of item 6770, further comprising a coating, wherein thecoating indirectly contacts the device.

6801. The device of item 6770, further comprising a coating, wherein thecoating partially covers the device.

6802. The device of item 6770, further comprising a coating, wherein thecoating completely covers the device.

6803. The device of item 6770, further comprising a coating, wherein thecoating is a uniform coating.

6804. The device of item 6770, further comprising a coating, wherein thecoating is a non-uniform coating.

6805. The device of item 6770, further comprising a coating, wherein thecoating is a discontinuous coating.

6806. The device of item 6770, further comprising a coating, wherein thecoating is a patterned coating.

6807. The device of item 6770, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

6808. The device of item 6770, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

6809. The device of item 6770, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

6810. The device of item 6770, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

6811. The device of item 6770, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

6812. The device of item 6770, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

6813. The device of item 6770, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

6814. The device of item 6770, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

6815. The device of item 6770, further comprising a coating, wherein thecoating further comprises a polymer.

6816. The device of item 6770, further comprising a first coating havinga first composition and the second coating having a second composition.

6817. The device of item 6770, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

6818. The device of item 6770, further comprising a polymer.

6819. The device of item 6770, further comprising a polymeric carrier.

6820. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

6821. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

6822. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

6823. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

6824. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

6825. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

6826. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

6827. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

6828. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

6829. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

6830. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

6831. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

6832. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

6833. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

6834. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

6835. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

6836. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

6837. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

6838. The device of item 6770, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

6839. The device of item 6770, further comprising a lubricious coating.

6840. The device of item 6770 wherein the fibrosing agent is locatedwithin pores or holes of the device.

6841. The device of item 6770 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

6842. The device of item 6770, further comprising a secondpharmaceutically active agent.

6843. The device of item 6770, further comprising an anti-inflammatoryagent.

6844. The device of item 6770, further comprising an agent that inhibitsinfection.

6845. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

6846. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

6847. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

6848. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

6849. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

6850. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

6851. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

6852. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

6853. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

6854. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

6855. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

6856. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

6857. The device of item 6770, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

6858. The device of item 6770, further comprising an anti-thromboticagent.

6859. The device of item 6770, further comprising a visualization agent.

6860. The device of item 6770, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

6861. The device of item 6770, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

6862. The device of item 6770, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

6863. The device of item 6770, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

6864. The device of item 6770, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

6865. The device of item 6770, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

6866. The device of item 6770, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

6867. The device of item 6770, further comprising an echogenic material.

6868. The device of item 6770, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

6869. The device of item 6770 wherein the device is sterile.

6870. The device of item 6770 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

6871. The device of item 6770 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

6872. The device of item 6770 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

6873. The device of item 6770 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

6874. The device of item 6770 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

6875. The device of item 6770 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

6876. The device of item 6770 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

6877. The device of item 6770 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

6878. The device of item 6770 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

6879. The device of item 6770 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

6880. The device of item 6770 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

6881. The device of item 6770 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

6882. The device of item 6770 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

6883. The device of item 6770 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

6884. The device of item 6770 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

6885. The device of item 6770 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

6886. The device of item 6770 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

6887. The device of item 6770 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

6888. The device of item 6770 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

6889. The device of item 6770 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6890. The device of item 6770 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6891. The device of item 6770 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6892. The device of item 6770 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

6893. The device of item 6770 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

6894. The device of item 6770 wherein the hernia mesh implant isexpandable.

6895. A medical device comprising a surgical film implant and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

6896. The device of item 6895 wherein the fibrosing agent promotesregeneration.

6897. The device of item 6895 wherein the fibrosing agent promotesangiogenesis.

6898. The device of item 6895 wherein the fibrosing agent promotesfibroblast migration.

6899. The device of item 6895 wherein the fibrosing agent promotesfibroblast proliferation.

6900. The device of item 6895 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

6901. The device of item 6895 wherein the fibrosing agent promotestissue remodeling.

6902. The device of item 6895 wherein the fibrosing agent is an arterialvessel wall irritant.

6903. The device of item 6895 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6904. The device of item 6895 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6905. The device of item 6895 wherein the fibrosing agent is orcomprises silk.

6906. The device of item 6895 wherein the fibrosing agent is orcomprises mineral particles.

6907. The device of item 6895 wherein the fibrosing agent is orcomprises chitosan.

6908. The device of item 6895 wherein the fibrosing agent is orcomprises polylysine.

6909. The device of item 6895 wherein the fibrosing agent is orcomprises fibronectin.

6910. The device of item 6895 wherein the fibrosing agent is orcomprises bleomycin.

6911. The device of item 6895 wherein the fibrosing agent is orcomprises CTGF.

6912. The device of item 6895 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

6913. The device of item 6895 wherein the fibrosing agent is in the formof a particulate.

6914. The device of item 6895 wherein the composition further comprisesan inflammatory cytokine.

6915. The device of item 6895 wherein the composition further comprisesan agent that stimulates cell proliferation.

6916. The device of item 6895 wherein the composition is in the form ofa gel, paste, or spray.

6917. The device of item 6895 wherein the fibrosing agent is in the formof tufts.

6918. The device of item 6895, further comprising a polymer.

6919. The device of item 6895, further comprising a polymeric carrier.

6920. The device of item 6895 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

6921. The device of item 6895 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

6922. The device of item 6895, further comprising a coating, wherein thecoating comprises the fibrosing agent.

6923. The device of item 6895, further comprising a coating, wherein thecoating is disposed on a surface of the device.

6924. The device of item 6895, further comprising a coating, wherein thecoating directly contacts the device.

6925. The device of item 6895, further comprising a coating, wherein thecoating indirectly contacts the device.

6926. The device of item 6895, further comprising a coating, wherein thecoating partially covers the device.

6927. The device of item 6895, further comprising a coating, wherein thecoating completely covers the device.

6928. The device of item 6895, further comprising a coating, wherein thecoating is a uniform coating.

6929. The device of item 6895, further comprising a coating, wherein thecoating is a non-uniform coating.

6930. The device of item 6895, further comprising a coating, wherein thecoating is a discontinuous coating.

6931. The device of item 6895, further comprising a coating, wherein thecoating is a patterned coating.

6932. The device of item 6895, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

6933. The device of item 6895, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

6934. The device of item 6895, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

6935. The device of item 6895, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

6936. The device of item 6895, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

6937. The device of item 6895, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

6938. The device of item 6895, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

6939. The device of item 6895, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

6940. The device of item 6895, further comprising a coating, wherein thecoating further comprises a polymer.

6941. The device of item 6895, further comprising a first coating havinga first composition and the second coating having a second composition.

6942. The device of item 6895, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

6943. The device of item 6895, further comprising a polymer.

6944. The device of item 6895, further comprising a polymeric carrier.

6945. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

6946. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

6947. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

6948. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

6949. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

6950. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

6951. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

6952. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

6953. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

6954. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

6955. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

6956. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

6957. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

6958. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

6959. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

6960. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

6961. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

6962. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

6963. The device of item 6895, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

6964. The device of item 6895, further comprising a lubricious coating.

6965. The device of item 6895 wherein the fibrosing agent is locatedwithin pores or holes of the device.

6966. The device of item 6895 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

6967. The device of item 6895, further comprising a secondpharmaceutically active agent.

6968. The device of item 6895, further comprising an anti-inflammatoryagent.

6969. The device of item 6895, further comprising an agent that inhibitsinfection.

6970. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

6971. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

6972. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

6973. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

6974. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

6975. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

6976. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

6977. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

6978. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

6979. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

6980. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

6981. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

6982. The device of item 6895, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

6983. The device of item 6895, further comprising an anti-thromboticagent.

6984. The device of item 6895, further comprising a visualization agent.

6985. The device of item 6895, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

6986. The device of item 6895, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

6987. The device of item 6895, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

6988. The device of item 6895, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

6989. The device of item 6895, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

6990. The device of item 6895, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

6991. The device of item 6895, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

6992. The device of item 6895, further comprising an echogenic material.

6993. The device of item 6895, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

6994. The device of item 6895 wherein the device is sterile.

6995. The device of item 6895 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

6996. The device of item 6895 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

6997. The device of item 6895 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

6998. The device of item 6895 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

6999. The device of item 6895 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

7000. The device of item 6895 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

7001. The device of item 6895 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

7002. The device of item 6895 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

7003. The device of item 6895 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

7004. The device of item 6895 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

7005. The device of item 6895 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

7006. The device of item 6895 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

7007. The device of item 6895 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

7008. The device of item 6895 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

7009. The device of item 6895 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

7010. The device of item 6895 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

7011. The device of item 6895 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

7012. The device of item 6895 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

7013. The device of item 6895 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

7014. The device of item 6895 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7015. The device of item 6895 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7016. The device of item 6895 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7017. The device of item 6895 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

7018. The device of item 6895 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7019. A medical device comprising a spinal fusion device and a fibrosingagent, where the fibrosing agent induces a fibrotic response between thedevice and a patient in which the device is implanted.

7020. The device of item 7019 wherein the fibrosing agent promotesregeneration.

7021. The device of item 7019 wherein the fibrosing agent promotesangiogenesis.

7022. The device of item 7019 wherein the fibrosing agent promotesfibroblast migration.

7023. The device of item 7019 wherein the fibrosing agent promotesfibroblast proliferation.

7024. The device of item 7019 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

7025. The device of item 7019 wherein the fibrosing agent promotestissue remodeling.

7026. The device of item 7019 wherein the fibrosing agent is an arterialvessel wall irritant.

7027. The device of item 7019 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7028. The device of item 7019 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7029. The device of item 7019 wherein the fibrosing agent is orcomprises silk.

7030. The device of item 7019 wherein the fibrosing agent is orcomprises mineral particles.

7031. The device of item 7019 wherein the fibrosing agent is orcomprises chitosan.

7032. The device of item 7019 wherein the fibrosing agent is orcomprises polylysine.

7033. The device of item 7019 wherein the fibrosing agent is orcomprises fibronectin.

7034. The device of item 7019 wherein the fibrosing agent is orcomprises bleomycin.

7035. The device of item 7019 wherein the fibrosing agent is orcomprises CTGF.

7036. The device of item 7019 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

7037. The device of item 7019 wherein the fibrosing agent is in the formof a particulate.

7038. The device of item 7019 wherein the composition further comprisesan inflammatory cytokine.

7039. The device of item 7019 wherein the composition further comprisesan agent that stimulates cell proliferation.

7040. The device of item 7019 wherein the composition is in the form ofa gel, paste, or spray.

7041. The device of item 7019 wherein the fibrosing agent is in the formof tufts.

7042. The device of item 7019, further comprising a polymer.

7043. The device of item 7019, further comprising a polymeric carrier.

7044. The device of item 7019 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7045. The device of item 7019 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7046. The device of item 7019, further comprising a coating, wherein thecoating comprises the fibrosing agent.

7047. The device of item 7019, further comprising a coating, wherein thecoating is disposed on a surface of the device.

7048. The device of item 7019, further comprising a coating, wherein thecoating directly contacts the device.

7049. The device of item 7019, further comprising a coating, wherein thecoating indirectly contacts the device.

7050. The device of item 7019, further comprising a coating, wherein thecoating partially covers the device.

7051. The device of item 7019, further comprising a coating, wherein thecoating completely covers the device.

7052. The device of item 7019, further comprising a coating, wherein thecoating is a uniform coating.

7053. The device of item 7019, further comprising a coating, wherein thecoating is a non-uniform coating.

7054. The device of item 7019, further comprising a coating, wherein thecoating is a discontinuous coating.

7055. The device of item 7019, further comprising a coating, wherein thecoating is a patterned coating.

7056. The device of item 7019, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

7057. The device of item 7019, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

7058. The device of item 7019, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

7059. The device of item 7019, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

7060. The device of item 7019, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

7061. The device of item 7019, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

7062. The device of item 7019, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

7063. The device of item 7019, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

7064. The device of item 7019, further comprising a coating, wherein thecoating further comprises a polymer.

7065. The device of item 7019, further comprising a first coating havinga first composition and the second coating having a second composition.

7066. The device of item 7019, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

7067. The device of item 7019, further comprising a polymer.

7068. The device of item 7019, further comprising a polymeric carrier.

7069. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

7070. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

7071. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

7072. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

7073. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

7074. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

7075. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

7076. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

7077. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

7078. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

7079. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

7080. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

7081. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

7082. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

7083. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

7084. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

7085. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

7086. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

7087. The device of item 7019, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

7088. The device of item 7019, further comprising a lubricious coating.

7089. The device of item 7019 wherein the fibrosing agent is locatedwithin pores or holes of the device.

7090. The device of item 7019 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

7091. The device of item 7019, further comprising a secondpharmaceutically active agent.

7092. The device of item 7019, further comprising an anti-inflammatoryagent.

7093. The device of item 7019, further comprising an agent that inhibitsinfection.

7094. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

7095. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

7096. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

7097. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

7098. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

7099. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

7100. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

7101. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

7102. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

7103. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

7104. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

7105. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

7106. The device of item 7019, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

7107. The device of item 7019, further comprising an anti-thromboticagent.

7108. The device of item 7019, further comprising a visualization agent.

7109. The device of item 7019, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

7110. The device of item 7019, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

7111. The device of item 7019, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

7112. The device of item 7019, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

7113. The device of item 7019, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

7114. The device of item 7019, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

7115. The device of item 7019, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

7116. The device of item 7019, further comprising an echogenic material.

7117. The device of item 7019, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

7118. The device of item 7019 wherein the device is sterile.

7119. The device of item 7019 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

7120. The device of item 7019 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

7121. The device of item 7019 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

7122. The device of item 7019 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

7123. The device of item 7019 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

7124. The device of item 7019 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

7125. The device of item 7019 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

7126. The device of item 7019 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

7127. The device of item 7019 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

7128. The device of item 7019 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

7129. The device of item 7019 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

7130. The device of item 7019 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

7131. The device of item 7019 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

7132. The device of item 7019 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

7133. The device of item 7019 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

7134. The device of item 7019 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

7135. The device of item 7019 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

7136. The device of item 7019 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

7137. The device of item 7019 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

7138. The device of item 7019 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7139. The device of item 7019 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7140. The device of item 7019 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7141. The device of item 7019 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

7142. The device of item 7019 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7143. The device of item 7019 wherein the spinal fusion device is afusion basket.

7144. The device of item 7019 wherein the spinal fusion device is afusion casge apparatus.

7145. The device of item 7019 wherein the spinal fusion device is aninterbody case.

7146. The device of item 7019 wherein the spinal fusion device is aninterbody implant.

7147. The device of item 7019 wherein the spinal fusion device is afusion cage anchoring device.

7148. The device of item 7019 wherein the spinal fusion device is afusion stabilization chamber.

7149. The device of item 7019 wherein the spinal fusion device is afusion cage anchoring plate.

7150. The device of item 7019 wherein the spinal fusion device is a bonefixation device.

7151. The device of item 7019 wherein the spinal fusion device is ananchoring bone plate.

7152. The device of item 7019 wherein the spinal fusion device is ananchoring bone screw.

7153. The device of item 7019 wherein the spinal fusion device is atissue filler.

7154. The device of item 7019 wherein the spinal fusion device is a bonecement.

7155. The device of item 7019 wherein the spinal fusion device is anallograft material.

7156. The device of item 7019 wherein the spinal fusion device is anautograft material.

7157. The device of item 7019 wherein the spinal fusion device is acollagen implant.

7158. The device of item 7019 wherein the spinal fusion device isinjectable.

7159. A medical device comprising a septal occlusion patch and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

7160. The device of item 7159 wherein the fibrosing agent promotesregeneration.

7161. The device of item 7159 wherein the fibrosing agent promotesangiogenesis.

7162. The device of item 7159 wherein the fibrosing agent promotesfibroblast migration.

7163. The device of item 7159 wherein the fibrosing agent promotesfibroblast proliferation.

7164. The device of item 7159 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

7165. The device of item 7159 wherein the fibrosing agent promotestissue remodeling.

7166. The device of item 7159 wherein the fibrosing agent is an arterialvessel wall irritant.

7167. The device of item 7159 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7168. The device of item 7159 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7169. The device of item 7159 wherein the fibrosing agent is orcomprises silk.

7170. The device of item 7159 wherein the fibrosing agent is orcomprises mineral particles.

7171. The device of item 7159 wherein the fibrosing agent is orcomprises chitosan.

7172. The device of item 7159 wherein the fibrosing agent is orcomprises polylysine.

7173. The device of item 7159 wherein the fibrosing agent is orcomprises fibronectin.

7174. The device of item 7159 wherein the fibrosing agent is orcomprises bleomycin.

7175. The device of item 7159 wherein the fibrosing agent is orcomprises CTGF.

7176. The device of item 7159 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

7177. The device of item 7159 wherein the fibrosing agent is in the formof a particulate.

7178. The device of item 7159 wherein the composition further comprisesan inflammatory cytokine.

7179. The device of item 7159 wherein the composition further comprisesan agent that stimulates cell proliferation.

7180. The device of item 7159 wherein the composition is in the form ofa gel, paste, or spray.

7181. The device of item 7159 wherein the fibrosing agent is in the formof tufts.

7182. The device of item 7159, further comprising a polymer.

7183. The device of item 7159, further comprising a polymeric carrier.

7184. The device of item 7159 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7185. The device of item 7159 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7186. The device of item 7159, further comprising a coating, wherein thecoating comprises the fibrosing agent.

7187. The device of item 7159, further comprising a coating, wherein thecoating is disposed on a surface of the device.

7188. The device of item 7159, further comprising a coating, wherein thecoating directly contacts the device.

7189. The device of item 7159, further comprising a coating, wherein thecoating indirectly contacts the device.

7190. The device of item 7159, further comprising a coating, wherein thecoating partially covers the device.

7191. The device of item 7159, further comprising a coating, wherein thecoating completely covers the device.

7192. The device of item 7159, further comprising a coating, wherein thecoating is a uniform coating.

7193. The device of item 7159, further comprising a coating, wherein thecoating is a non-uniform coating.

7194. The device of item 7159, further comprising a coating, wherein thecoating is a discontinuous coating.

7195. The device of item 7159, further comprising a coating, wherein thecoating is a patterned coating.

7196. The device of item 7159, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

7197. The device of item 7159, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

7198. The device of item 7159, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

7199. The device of item 7159, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

7200. The device of item 7159, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

7201. The device of item 7159, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

7202. The device of item 7159, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

7203. The device of item 7159, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

7204. The device of item 7159, further comprising a coating, wherein thecoating further comprises a polymer.

7205. The device of item 7159, further comprising a first coating havinga first composition and the second coating having a second composition.

7206. The device of item 7159, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

7207. The device of item 7159, further comprising a polymer.

7208. The device of item 7159, further comprising a polymeric carrier.

7209. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

7210. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

7211. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

7212. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

7213. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

7214. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

7215. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

7216. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

7217. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

7218. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

7219. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

7220. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

7221. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

7222. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

7223. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

7224. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

7225. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

7226. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

7227. The device of item 7159, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

7228. The device of item 7159, further comprising a lubricious coating.

7229. The device of item 7159 wherein the fibrosing agent is locatedwithin pores or holes of the device.

7230. The device of item 7159 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

7231. The device of item 7159, further comprising a secondpharmaceutically active agent.

7232. The device of item 7159, further comprising an anti-inflammatoryagent.

7233. The device of item 7159, further comprising an agent that inhibitsinfection.

7234. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

7235. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

7236. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

7237. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

7238. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

7239. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

7240. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

7241. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

7242. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

7243. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

7244. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

7245. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

7246. The device of item 7159, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

7247. The device of item 7159, further comprising an anti-thromboticagent.

7248. The device of item 7159, further comprising a visualization agent.

7249. The device of item 7159, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

7250. The device of item 7159, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

7251. The device of item 7159, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

7252. The device of item 7159, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

7253. The device of item 7159, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

7254. The device of item 7159, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

7255. The device of item 7159, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

7256. The device of item 7159, further comprising an echogenic material.

7257. The device of item 7159, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

7258. The device of item 7159 wherein the device is sterile.

7259. The device of item 7159 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

7260. The device of item 7159 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

7261. The device of item 7159 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

7262. The device of item 7159 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

7263. The device of item 7159 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

7264. The device of item 7159 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

7265. The device of item 7159 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

7266. The device of item 7159 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

7267. The device of item 7159 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

7268. The device of item 7159 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

7269. The device of item 7159 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

7270. The device of item 7159 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

7271. The device of item 7159 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

7272. The device of item 7159 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

7273. The device of item 7159 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

7274. The device of item 7159 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

7275. The device of item 7159 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

7276. The device of item 7159 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

7277. The device of item 7159 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

7278. The device of item 7159 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7279. The device of item 7159 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7280. The device of item 7159 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7281. The device of item 7159 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

7282. The device of item 7159 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7283. The device of item 7159 wherein the septal occlusion patch is aseptal closure device.

7284. The device of item 7159 wherein the septal occlusion patch is ashunt closure device.

7285. The device of item 7159 wherein the septal occlusion patch is anintracardic occluder.

7286. The device of item 7159 wherein the septal occlusion patch is anoccluding disk.

7287. The device of item 7159 wherein the septal occlusion patch is adefect occluding system.

7288. The device of item 7159 wherein the septal occlusion patch is anintravascular shunt device.

7289. A medical device comprising an endoluminal fasterner and afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

7290. The device of item 7289 wherein the fibrosing agent promotesregeneration.

7291. The device of item 7289 wherein the fibrosing agent promotesangiogenesis.

7292. The device of item 7289 wherein the fibrosing agent promotesfibroblast migration.

7293. The device of item 7289 wherein the fibrosing agent promotesfibroblast proliferation.

7294. The device of item 7289 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

7295. The device of item 7289 wherein the fibrosing agent promotestissue remodeling.

7296. The device of item 7289 wherein the fibrosing agent is an arterialvessel wall irritant.

7297. The device of item 7289 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7298. The device of item 7289 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7299. The device of item 7289 wherein the fibrosing agent is orcomprises silk.

7300. The device of item 7289 wherein the fibrosing agent is orcomprises mineral particles.

7301. The device of item 7289 wherein the fibrosing agent is orcomprises chitosan.

7302. The device of item 7289 wherein the fibrosing agent is orcomprises polylysine.

7303. The device of item 7289 wherein the fibrosing agent is orcomprises fibronectin.

7304. The device of item 7289 wherein the fibrosing agent is orcomprises bleomycin.

7305. The device of item 7289 wherein the fibrosing agent is orcomprises CTGF.

7306. The device of item 7289 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

7307. The device of item 7289 wherein the fibrosing agent is in the formof a particulate.

7308. The device of item 7289 wherein the composition further comprisesan inflammatory cytokine.

7309. The device of item 7289 wherein the composition further comprisesan agent that stimulates cell proliferation.

7310. The device of item 7289 wherein the composition is in the form ofa gel, paste, or spray.

7311. The device of item 7289 wherein the fibrosing agent is in the formof tufts.

7312. The device of item 7289, further comprising a polymer.

7313. The device of item 7289, further comprising a polymeric carrier.

7314. The device of item 7289 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7315. The device of item 7289 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7316. The device of item 7289, further comprising a coating, wherein thecoating comprises the fibrosing agent.

7317. The device of item 7289, further comprising a coating, wherein thecoating is disposed on a surface of the device.

7318. The device of item 7289, further comprising a coating, wherein thecoating directly contacts the device.

7319. The device of item 7289, further comprising a coating, wherein thecoating indirectly contacts the device.

7320. The device of item 7289, further comprising a coating, wherein thecoating partially covers the device.

7321. The device of item 7289, further comprising a coating, wherein thecoating completely covers the device.

7322. The device of item 7289, further comprising a coating, wherein thecoating is a uniform coating.

7323. The device of item 7289, further comprising a coating, wherein thecoating is a non-uniform coating.

7324. The device of item 7289, further comprising a coating, wherein thecoating is a discontinuous coating.

7325. The device of item 7289, further comprising a coating, wherein thecoating is a patterned coating.

7326. The device of item 7289, further comprising a coating, wherein thecoating has a thickness of 100 μm or less.

7327. The device of item 7289, further comprising a coating, wherein thecoating has a thickness of 10 μm or less.

7328. The device of item 7289, further comprising a coating, wherein thecoating adheres to the surface of the device upon deployment of thedevice.

7329. The device of item 7289, further comprising a coating, wherein thecoating is stable at room temperature for a period of 1 year.

7330. The device of item 7289, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 0.0001% to about 1% by weight.

7331. The device of item 7289, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 1% to about 10% by weight.

7332. The device of item 7289, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 10% to about 25% by weight.

7333. The device of item 7289, further comprising a coating, wherein thefibrosing agent is present in the coating in an amount ranging betweenabout 25% to about 70% by weight.

7334. The device of item 7289, further comprising a coating, wherein thecoating further comprises a polymer.

7335. The device of item 7289, further comprising a first coating havinga first composition and the second coating having a second composition.

7336. The device of item 7289, further comprising a first coating havinga first composition and the second coating having a second composition,wherein the first composition and the second composition are different.

7337. The device of item 7289, further comprising a polymer.

7338. The device of item 7289, further comprising a polymeric carrier.

7339. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a copolymer.

7340. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a block copolymer.

7341. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a random copolymer.

7342. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a biodegradable polymer.

7343. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-biodegradable polymer.

7344. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophilic polymer.

7345. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrophobic polymer.

7346. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophilicdomains.

7347. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a polymer having hydrophobicdomains.

7348. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a non-conductive polymer.

7349. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises an elastomer.

7350. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrogel.

7351. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a silicone polymer.

7352. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a hydrocarbon polymer.

7353. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a styrene-derived polymer.

7354. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a butadiene polymer.

7355. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a macromer.

7356. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises a poly(ethylene glycol) polymer.

7357. The device of item 7289, further comprising a polymeric carrier,wherein the polymeric carrier comprises an amorphous polymer.

7358. The device of item 7289, further comprising a lubricious coating.

7359. The device of item 7289 wherein the fibrosing agent is locatedwithin pores or holes of the device.

7360. The device of item 7289 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

7361. The device of item 7289, further comprising a secondpharmaceutically active agent.

7362. The device of item 7289, further comprising an anti-inflammatoryagent.

7363. The device of item 7289, further comprising an agent that inhibitsinfection.

7364. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is an anthracycline.

7365. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is doxorubicin.

7366. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is mitoxantrone.

7367. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is a fluoropyrimidine.

7368. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is 5-fluorouracil (5-FU).

7369. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is a folic acid antagonist.

7370. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is methotrexate.

7371. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is a podophylotoxin.

7372. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is etoposide.

7373. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is a camptothecin.

7374. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is a hydroxyurea.

7375. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is a platinum complex.

7376. The device of item 7289, further comprising an agent that inhibitsinfection, wherein the agent is cisplatin.

7377. The device of item 7289, further comprising an anti-thromboticagent.

7378. The device of item 7289, further comprising a visualization agent.

7379. The device of item 7289, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises a metal, a halogenated compound, or abarium containing compound.

7380. The device of item 7289, further comprising a visualization agent,wherein the visualization agent is a radiopaque material, wherein theradiopaque material comprises barium, tantalum, or technetium.

7381. The device of item 7289, further comprising a visualization agent,wherein the visualization agent is a MRI responsive material.

7382. The device of item 7289, further comprising a visualization agent,wherein the visualization agent comprises a gadolinium chelate.

7383. The device of item 7289, further comprising a visualization agent,wherein the visualization agent comprises iron, magnesium, manganese,copper, or chromium.

7384. The device of item 7289, further comprising a visualization agent,wherein the visualization agent comprises an iron oxide compound.

7385. The device of item 7289, further comprising a visualization agent,wherein the visualization agent comprises a dye, pigment, or colorant.

7386. The device of item 7289, further comprising an echogenic material.

7387. The device of item 7289, further comprising an echogenic material,wherein the echogenic material is in the form of a coating.

7388. The device of item 7289 wherein the device is sterile.

7389. The device of item 7289 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

7390. The device of item 7289 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

7391. The device of item 7289 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

7392. The device of item 7289 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

7393. The device of item 7289 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

7394. The device of item 7289 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

7395. The device of item 7289 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

7396. The device of item 7289 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

7397. The device of item 7289 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

7398. The device of item 7289 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

7399. The device of item 7289 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

7400. The device of item 7289 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

7401. The device of item 7289 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

7402. The device of item 7289 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

7403. The device of item 7289 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

7404. The device of item 7289 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

7405. The device of item 7289 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

7406. The device of item 7289 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

7407. The device of item 7289 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

7408. The device of item 7289 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7409. The device of item 7289 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7410. The device of item 7289 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7411. The device of item 7289 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

7412. The device of item 7289 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7413. A method of making an injectable composition comprising combininga fibrosing agent and a bulking agent.

7414. The method of item 7413 wherein the fibrosing agent promotesfibrosis and promotes regeneration.

7415. The method of item 7413 wherein the fibrosing agent promotesangiogenesis.

7416. The method of item 7413 wherein the fibrosing agent promotesfibroblast migration.

7417. The method of item 7413 wherein the fibrosing agent promotesfibroblast proliferation.

7418. The method of item 7413 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

7419. The method of item 7413 wherein the fibrosing agent promotestissue remodeling.

7420. The method of item 7413 wherein the fibrosing agent is orcomprises an arterial vessel wall irritant.

7421. The method of item 7413 wherein the fibrosing agent is orcomprises silk.

7422. The method of item 7413 wherein the fibrosing agent is orcomprises silkworm silk.

7423. The method of item 7413 wherein the fibrosing agent is orcomprises spider silk.

7424. The method of item 7413 wherein the fibrosing agent is orcomprises recombinant silk.

7425. The method of item 7413 wherein the fibrosing agent is orcomprises raw silk.

7426. The method of item 7413 wherein the fibrosing agent is orcomprises hydrolyzed silk.

7427. The method of item 7413 wherein the fibrosing agent is orcomprises acid-treated silk.

7428. The method of item 7413 wherein the fibrosing agent is orcomprises acylated silk.

7429. The method of item 7413 wherein the fibrosing agent is in the formof strands.

7430. The method of item 7413 wherein the fibrosing agent is in the formof tufts.

7431. The method of item 7413 wherein the fibrosing agent is in the formof microparticulates.

7432. The method of item 7413 wherein the fibrosing agent is orcomprises mineral particles.

7433. The method of item 7413 wherein the fibrosing agent is orcomprises talc.

7434. The method of item 7413 wherein the fibrosing agent is orcomprises chitosan.

7435. The method of item 7413 wherein the fibrosing agent is orcomprises polylysine.

7436. The method of item 7413 wherein the fibrosing agent is orcomprises fibronectin.

7437. The method of item 7413 wherein the fibrosing agent is orcomprises bleomycin.

7438. The method of item 7413 wherein the fibrosing agent is orcomprises CTGF.

7439. The method of item 7413 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

7440. The method of item 7439 wherein the thread is biodegradable.

7441. The method of item 7440 wherein the biodegradable thread comprisesa material selected from the group consisting of polyester,polyanhydride, poly(anhydride ester), poly(ester-amide),poly(ester-urea), polyorthoester, polyphosphoester, polyphosphazine,polycyanoacrylate, collagen, chitosan, hyaluronic acid, chromic cat gut,alginate, starch, cellulose and cellulose ester.

7442. The method of item 7439 wherein the thread is non-biodegradable.

7443. The method of item 7442 wherein the non-non-bioderadable threadcomprises a material selected from the group consisting of polyester,polyurethane, silicone, polyethylene, polypropylene, polystyrene,polyacrylate, polymethacrylate, and silk.

7444. The method of item 7439 wherein the thread is coated with apolymer.

7445. The method of item 7439 wherein the thread is coated with apharmaceutical agent that induces a fibrotic response in the patient.

7446. The method of item 7439 wherein the thread is coated with apharmaceutical agent that induces an osteogenic response in the patient.

7447. The method of item 7413 wherein the fibrosing agent is in the formof a particulate.

7448. The method of item 7447 wherein the particulate is a biodegradableparticulate.

7449. The method of item 7448 wherein the biodegradable particulatecomprises a material selected from the group consisting of polyester,polyanhydride, poly(anhydride ester), poly(ester-amide),poly(ester-urea), polyorthoester, polyphosphoester, polyphosphazine,polycyanoacrylate, collagen, chitosan, hyaluronic acid, chromic cat gut,alginate, starch, cellulose and cellulose ester.

7450. The method of item 7447 wherein the particulate isnon-biodegradable.

7451. The method of item 7450 wherein the non-biodegradable particulatecomprises a material selected from the group consisting of polyester,polyurethane, silicone, polyethylene, polypropylene, polystyrene,polyacrylate, polymethacrylate, and silk.

7452. The method of item 7447 wherein the particulate is a particulateform of a member selected from the group consisting of silk, talc,starch, glass, silicate, silica, calcium phosphate, calcium sulfate,calcium carbonate, hydroxyapatite, synthetic mineral,polymethylmethacrylate, silver nitrate, ceramic and other inorganicparticles.

7453. The method of item 7447 wherein the particulate is coated with apolymer.

7454. The method of item 7447 wherein the particulate is coated with apharmaceutical agent that induces a fibrotic response in the patient.

7455. The method of item 7447 wherein the particulate is coated with amember selected from the group consisting of silk, talc, starch, glass,silicate, silica, calcium phosphate, calcium sulfate, calcium carbonate,hydroxyapatite, synthetic mineral, polymethylmethacrylate, silvernitrate, ceramic and other inorganic particles.

7456. The method of item 7447 wherein the particulate is coated with apharmaceutical agent that induces an osteogenic response in the patient.

7457. The method of item 7413 wherein the composition further comprisesan agent that promotes bone growth.

7458. The method of item 7457 wherein the agent that promotes bonegrowth is a bone morphogenic protein.

7459. The method of item 7457 wherein the agent that promotes bonegrowth is an osteogenic growth factor.

7460. The method of item 7459 wherein the osteogenic growth factor isselected from transforming growth factor, platelet-derived growthfactor, and fibroblast growth factor.

7461. The method of item 7413 wherein the bulking agent comprisescollagen or crosslinked collagen.

7462. The method of item 7413 wherein the bulking agent compriseshydroxya patite.

7463. The method of item 7413 wherein the bulking agent comprisesmicronized alloderm acellular matrix.

7464. The method of item 7413 wherein the bulking agent compriseshyaluronic acid.

7465. The method of item 7413 wherein the bulking agent is a hydrogel.

7466. The method of item 7413 wherein the bulking agent comprisesbeta-glucan.

7467. The method of item 7413 wherein the bulking agent comprisescollagen fibrils.

7468. The method of item 7413 wherein the bulking agent comprises hylanpolymer.

7469. The method of item 7413 wherein the bulking agent comprisesmicrospheres.

7470. The method of item 7413 wherein the bulking agent comprisespolyacrylic acid or polyacrylate.

7471. The method of item 7413 wherein the bulking agent comprisessilicon or crosslinked silicon.

7472. The method of item 7413 wherein a visualization agent is combinedwith the fibrosing agent and/or the bulking agent.

7473. The method of item 7413 wherein a coloring agent is combined withthe fibrosing agent and/or the bulking agent.

7474. The method of item 7413 wherein the composition is treated toprovide a sterile composition.

7475. The method of item 7413 wherein the composition is formulated tobe an urethral bulking agent.

7476. The method of item 7413 wherein the composition is formulated tobe an esophageal bulking agent.

7477. The method of item 7413 wherein the composition is formulated tobe an anal bulking agent.

7478. The method of item 7413 wherein the fibrosing agent is present inthe composition at a concentration within the range of about 0.005 μg-10μg per mm³.

7479. A method of making a medical device comprising combining i) anorthopedic implant and ii) a fibrosing agent or a composition comprisinga fibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

7480. The method of item 7479 wherein the fibrosing agent promotesregeneration.

7481. The method of item 7479 wherein the fibrosing agent promotesangiogenesis.

7482. The method of item 7479 wherein the fibrosing agent promotesfibroblast migration.

7483. The method of item 7479 wherein the fibrosing agent promotesfibroblast proliferation.

7484. The method of item 7479 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

7485. The method of item 7479 wherein the fibrosing agent promotestissue remodeling.

7486. The method of item 7479 wherein the fibrosing agent is an arterialvessel wall irritant.

7487. The method of item 7479 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7488. The method of item 7479 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7489. The method of item 7479 wherein the fibrosing agent is orcomprises silk.

7490. The method of item 7479 wherein the fibrosing agent is orcomprises mineral particles.

7491. The method of item 7479 wherein the fibrosing agent is orcomprises chitosan.

7492. The method of item 7479 wherein the fibrosing agent is orcomprises polylysine.

7493. The method of item 7479 wherein the fibrosing agent is orcomprises fibronectin.

7494. The method of item 7479 wherein the fibrosing agent is orcomprises bleomycin.

7495. The method of item 7479 wherein the fibrosing agent is orcomprises CTGF.

7496. The method of item 7479 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

7497. The method of item 7479 wherein the fibrosing agent is in the formof a particulate.

7498. The method of item 7479 wherein the composition further comprisesan inflammatory cytokine.

7499. The method of item 7479 wherein the composition further comprisesan agent that stimulates cell proliferation.

7500. The method of item 7479 wherein the composition is in the form ofa gel or paste.

7501. The method of item 7479 wherein the fibrosing agent is in the formof tufts.

7502. The method of item 7479 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7503. The method of item 7479 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7504. The method of item 7479, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

7505. The method of item 7479, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

7506. The method of item 7479, wherein the implant is combined with acoating, and the coating directly contacts the device.

7507. The method of item 7479, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

7508. The method of item 7479, wherein the implant is combined with acoating, and the coating partially covers the device.

7509. The method of item 7479, wherein the implant is combined with acoating, and the coating completely covers the device.

7510. The method of item 7479, wherein the implant is combined with acoating, and the coating is a uniform coating.

7511. The method of item 7479, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

7512. The method of item 7479, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

7513. The method of item 7479 wherein the implant is combined with acoating, and the coating is a patterned coating.

7514. The method of item 7479, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

7515. The method of item 7479, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

7516. The method of item 7479, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

7517. The method of item 7479, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

7518. The method of item 7479, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

7519. The method of item 7479, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

7520. The method of item 7479, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

7521. The method of item 7479, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

7522. The method of item 7479, wherein the implant is combined with acoating, and the coating further comprises a polymer.

7523. The method of item 7479, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

7524. The method of item 7479, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

7525. The method of item 7479, wherein the device comprises a polymer.

7526. The method of item 7479, wherein the device comprises a polymer,and the polymer is a component of the composition.

7527. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a copolymer.

7528. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

7529. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

7530. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

7531. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

7532. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

7533. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

7534. The method of item 7479, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

7535. The method of item 7479, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

7536. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

7537. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is an elastomer.

7538. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

7539. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

7540. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

7541. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

7542. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

7543. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a macromer.

7544. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

7545. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

7546. The method of item 7479, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

7547. The method of item 7479 wherein the fibrosing agent is locatedwithin pores or holes of the device.

7548. The method of item 7479 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

7549. The method of item 7479, wherein the implant is further combinedwith a second pharmaceutically active agent.

7550. The method of item 7479, wherein the implant is further combinedwith an anti-inflammatory agent.

7551. The method of item 7479 wherein the implant is further combinedwith an agent that inhibits infection.

7552. The method of item 7479, wherein the implant is further combinedwith an anthracycline.

7553. The method of item 7479, wherein the implant is further combinedwith doxorubicin.

7554. The method of item 7479, wherein the implant is further combinedwith mitoxantrone.

7555. The method of item 7479, wherein the implant is further combinedwith a fluoropyrimidine.

7556. The method of item 7479, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

7557. The method of item 7479, wherein the implant is further combinedwith a folic acid antagonist.

7558. The method of item 7479, wherein the implant is further combinedwith methotrexate.

7559. The method of item 7479, wherein the implant is further combinedwith a podophylotoxin.

7560. The method of item 7479, wherein the implant is further combinedwith etoposide.

7561. The method of item 7479 wherein the implant is further combinedwith a camptothecin.

7562. The method of item 7479, wherein the implant is further combinedwith a hydroxyurea.

7563. The method of item 7479, wherein the implant is further combinedwith a platinum complex.

7564. The method of item 7479, wherein the implant is further combinedwith cisplatin.

7565. The method of item 7479, wherein the implant is further combinedwith an anti-thrombotic agent.

7566. The method of item 7479, wherein the implant is further combinedwith a visualization agent.

7567. The method of item 7479, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

7568. The method of item 7479, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

7569. The method of item 7479, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

7570. The method of item 7479, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

7571. The method of item 7479, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

7572. The method of item 7479, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

7573. The method of item 7479, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

7574. The method of item 7479, wherein the implant is further combinedwith an echogenic material.

7575. The method of item 7479, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

7576. The method of item 7479 wherein the device is sterilized.

7577. The method of item 7479 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

7578. The method of item 7479 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

7579. The method of item 7479 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

7580. The method of item 7479 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

7581. The method of item 7479 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

7582. The method of item 7479 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

7583. The method of item 7479 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

7584. The method of item 7479 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

7585. The method of item 7479 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

7586. The method of item 7479 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

7587. The method of item 7479 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

7588. The method of item 7479 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

7589. The method of item 7479 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

7590. The method of item 7479 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

7591. The method of item 7479 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

7592. The method of item 7479 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

7593. The method of item 7479 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

7594. The method of item 7479 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

7595. The method of item 7479 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

7596. The method of item 7479 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7597. The method of item 7479 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7598. The method of item 7479 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7599. The method of item 7479 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

7600. The method of item 7479 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7601. The method of item 7479 wherein the orthopedic implant is used asa substitute for a bone graft.

7602. The method of item 7479 wherein the orthopedic implant is anorthopedic pin implant.

7603. The method of item 7479 wherein the orthopedic implant is anorthopedic nail implant.

7604. A method of making a medical device comprising combining i) anorthopedic prosthesis and ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

7605. The method of item 7604 wherein the fibrosing agent promotesregeneration.

7606. The method of item 7604 wherein the fibrosing agent promotesangiogenesis.

7607. The method of item 7604 wherein the fibrosing agent promotesfibroblast migration.

7608. The method of item 7604 wherein the fibrosing agent promotesfibroblast proliferation.

7609. The method of item 7604 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

7610. The method of item 7604 wherein the fibrosing agent promotestissue remodeling.

7611. The method of item 7604 wherein the fibrosing agent is an arterialvessel wall irritant.

7612. The method of item 7604 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7613. The method of item 7604 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7614. The method of item 7604 wherein the fibrosing agent is orcomprises silk.

7615. The method of item 7604 wherein the fibrosing agent is orcomprises mineral particles.

7616. The method of item 7604 wherein the fibrosing agent is orcomprises chitosan.

7617. The method of item 7604 wherein the fibrosing agent is orcomprises polylysine.

7618. The method of item 7604 wherein the fibrosing agent is orcomprises fibronectin.

7619. The method of item 7604 wherein the fibrosing agent is orcomprises bleomycin.

7620. The method of item 7604 wherein the fibrosing agent is orcomprises CTGF.

7621. The method of item 7604 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

7622. The method of item 7604 wherein the fibrosing agent is in the formof a particulate.

7623. The method of item 7604 wherein the composition further comprisesan inflammatory cytokine.

7624. The method of item 7604 wherein the composition further comprisesan agent that stimulates cell proliferation.

7625. The method of item 7604 wherein the composition is in the form ofa gel or paste.

7626. The method of item 7604 wherein the fibrosing agent is in the formof tufts.

7627. The method of item 7604 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7628. The method of item 7604 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7629. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating comprises the fibrosing agent.

7630. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating is disposed on a surface of the device.

7631. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating directly contacts the device.

7632. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating indirectly contacts the device.

7633. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating partially covers the device.

7634. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating completely covers the device.

7635. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating is a uniform coating.

7636. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating is a non-uniform coating.

7637. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating is a discontinuous coating.

7638. The method of item 7604 wherein the prosthesis is combined with acoating, and the coating is a patterned coating.

7639. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating has a thickness of 100 μm or less.

7640. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating has a thickness of 10 μm or less.

7641. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

7642. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

7643. The method of item 7604, wherein the prosthesis is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

7644. The method of item 7604, wherein the prosthesis is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

7645. The method of item 7604, wherein the prosthesis is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

7646. The method of item 7604, wherein the prosthesis is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

7647. The method of item 7604, wherein the prosthesis is combined with acoating, and the coating further comprises a polymer.

7648. The method of item 7604, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

7649. The method of item 7604, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

7650. The method of item 7604, wherein the device comprises a polymer.

7651. The method of item 7604, wherein the device comprises a polymer,and the polymer is a component of the composition.

7652. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a copolymer.

7653. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a block copolymer.

7654. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a random copolymer.

7655. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a biodegradable polymer.

7656. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a non-biodegradable polymer.

7657. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a hydrophilic polymer.

7658. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a hydrophobic polymer.

7659. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer has hydrophilic domains.

7660. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer has hydrophobic domains.

7661. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a non-conductive polymer.

7662. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is an elastomer.

7663. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a hydrogel.

7664. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a silicone polymer.

7665. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a hydrocarbon polymer.

7666. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a styrene-derived polymer.

7667. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a butadiene polymer.

7668. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a macromer.

7669. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

7670. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is an amorphous polymer.

7671. The method of item 7604, wherein the prosthesis is combined with apolymer, and the polymer is a lubricious coating.

7672. The method of item 7604 wherein the fibrosing agent is locatedwithin pores or holes of the device.

7673. The method of item 7604 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

7674. The method of item 7604, wherein the prosthesis is furthercombined with a second pharmaceutically active agent.

7675. The method of item 7604, wherein the prosthesis is furthercombined with an anti-inflammatory agent.

7676. The method of item 7604 wherein the prosthesis is further combinedwith an agent that inhibits infection.

7677. The method of item 7604, wherein the prosthesis is furthercombined with an anthracycline.

7678. The method of item 7604, wherein the prosthesis is furthercombined with doxorubicin.

7679. The method of item 7604, wherein the prosthesis is furthercombined with mitoxantrone.

7680. The method of item 7604, wherein the prosthesis is furthercombined with a fluoropyrimidine.

7681. The method of item 7604, wherein the prosthesis is furthercombined with 5-fluorouracil (5-FU).

7682. The method of item 7604, wherein the prosthesis is furthercombined with a folic acid antagonist.

7683. The method of item 7604, wherein the prosthesis is furthercombined with methotrexate.

7684. The method of item 7604, wherein the prosthesis is furthercombined with a podophylotoxin.

7685. The method of item 7604, wherein the prosthesis is furthercombined with etoposide.

7686. The method of item 7604 wherein the prosthesis is further combinedwith a camptothecin.

7687. The method of item 7604, wherein the prosthesis is furthercombined with a hydroxyurea.

7688. The method of item 7604, wherein the prosthesis is furthercombined with a platinum complex.

7689. The method of item 7604, wherein the prosthesis is furthercombined with cisplatin.

7690. The method of item 7604, wherein the prosthesis is furthercombined with an anti-thrombotic agent.

7691. The method of item 7604, wherein the prosthesis is furthercombined with a visualization agent.

7692. The method of item 7604, wherein the prosthesis is furthercombined with a visualization agent, wherein the visualization agent isa radiopaque material, wherein the radiopaque material comprises ametal, a halogenated compound, or a barium containing compound.

7693. The method of item 7604, wherein the prosthesis is furthercombined with a visualization agent, wherein the visualization agent isa radiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

7694. The method of item 7604, wherein the prosthesis is furthercombined with a visualization agent, wherein the visualization agent isa MRI responsive material.

7695. The method of item 7604, wherein the prosthesis is furthercombined with a visualization agent, wherein the visualization agentcomprises a gadolinium chelate.

7696. The method of item 7604, wherein the prosthesis is furthercombined with a visualization agent, wherein the visualization agentcomprises iron, magnesium, manganese, copper, or chromium.

7697. The method of item 7604, wherein the prosthesis is furthercombined with a visualization agent, wherein the visualization agentcomprises an iron oxide compound.

7698. The method of item 7604, wherein the prosthesis is furthercombined with a visualization agent, wherein the visualization agentcomprises a dye, pigment, or colorant.

7699. The method of item 7604, wherein the prosthesis is furthercombined with an echogenic material.

7700. The method of item 7604, wherein the prosthesis is furthercombined with an echogenic material, and the echogenic material is inthe form of a coating.

7701. The method of item 7604 wherein the device is sterilized.

7702. The method of item 7604 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

7703. The method of item 7604 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

7704. The method of item 7604 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

7705. The method of item 7604 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

7706. The method of item 7604 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

7707. The method of item 7604 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

7708. The method of item 7604 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

7709. The method of item 7604 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

7710. The method of item 7604 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

7711. The method of item 7604 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

7712. The method of item 7604 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

7713. The method of item 7604 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

7714. The method of item 7604 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

7715. The method of item 7604 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

7716. The method of item 7604 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

7717. The method of item 7604 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

7718. The method of item 7604 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

7719. The method of item 7604 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

7720. The method of item 7604 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

7721. The method of item 7604 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7722. The method of item 7604 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7723. The method of item 7604 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7724. The method of item 7604 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

7725. The method of item 7604 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7726. The method of item 7604 wherein the orthopedic implant is a kneeimplant.

7727. The method of item 7604 wherein the orthopedic implant is hipimplant.

7728. The method of item 7604 wherein the orthopedic implant is ashoulder implant.

7729. The method of item 7604 wherein the orthopedic implant is a digitimplant.

7730. A method of making a medical device comprising combining i) adental implant and ii) a fibrosing agent or a composition comprising afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

7731. The method of item 7730 wherein the fibrosing agent promotesregeneration.

7732. The method of item 7730 wherein the fibrosing agent promotesangiogenesis.

7733. The method of item 7730 wherein the fibrosing agent promotesfibroblast migration.

7734. The method of item 7730 wherein the fibrosing agent promotesfibroblast proliferation.

7735. The method of item 7730 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

7736. The method of item 7730 wherein the fibrosing agent promotestissue remodeling.

7737. The method of item 7730 wherein the fibrosing agent is an arterialvessel wall irritant.

7738. The method of item 7730 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7739. The method of item 7730 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7740. The method of item 7730 wherein the fibrosing agent is orcomprises silk.

7741. The method of item 7730 wherein the fibrosing agent is orcomprises mineral particles.

7742. The method of item 7730 wherein the fibrosing agent is orcomprises chitosan.

7743. The method of item 7730 wherein the fibrosing agent is orcomprises polylysine.

7744. The method of item 7730 wherein the fibrosing agent is orcomprises fibronectin.

7745. The method of item 7730 wherein the fibrosing agent is orcomprises bleomycin.

7746. The method of item 7730 wherein the fibrosing agent is orcomprises CTGF.

7747. The method of item 7730 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

7748. The method of item 7730 wherein the fibrosing agent is in the formof a particulate.

7749. The method of item 7730 wherein the composition further comprisesan inflammatory cytokine.

7750. The method of item 7730 wherein the composition further comprisesan agent that stimulates cell proliferation.

7751. The method of item 7730 wherein the composition is in the form ofa gel or paste.

7752. The method of item 7730 wherein the fibrosing agent is in the formof tufts.

7753. The method of item 7730 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7754. The method of item 7730 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7755. The method of item 7730, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

7756. The method of item 7730, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

7757. The method of item 7730, wherein the implant is combined with acoating, and the coating directly contacts the device.

7758. The method of item 7730, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

7759. The method of item 7730, wherein the implant is combined with acoating, and the coating partially covers the device.

7760. The method of item 7730, wherein the implant is combined with acoating, and the coating completely covers the device.

7761. The method of item 7730, wherein the implant is combined with acoating, and the coating is a uniform coating.

7762. The method of item 7730, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

7763. The method of item 7730, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

7764. The method of item 7730 wherein the implant is combined with acoating, and the coating is a patterned coating.

7765. The method of item 7730, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

7766. The method of item 7730, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

7767. The method of item 7730, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

7768. The method of item 7730, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

7769. The method of item 7730, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

7770. The method of item 7730, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

7771. The method of item 7730, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

7772. The method of item 7730, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

7773. The method of item 7730, wherein the implant is combined with acoating, and the coating further comprises a polymer.

7774. The method of item 7730, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

7775. The method of item 7730, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

7776. The method of item 7730, wherein the device comprises a polymer.

7777. The method of item 7730, wherein the device comprises a polymer,and the polymer is a component of the composition.

7778. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a copolymer.

7779. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

7780. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

7781. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

7782. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

7783. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

7784. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

7785. The method of item 7730, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

7786. The method of item 7730, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

7787. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

7788. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is an elastomer.

7789. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

7790. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

7791. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

7792. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

7793. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

7794. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a macromer.

7795. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

7796. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

7797. The method of item 7730, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

7798. The method of item 7730 wherein the fibrosing agent is locatedwithin pores or holes of the device.

7799. The method of item 7730 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

7800. The method of item 7730, wherein the implant is further combinedwith a second pharmaceutically active agent.

7801. The method of item 7730, wherein the implant is further combinedwith an anti-inflammatory agent.

7802. The method of item 7730 wherein the implant is further combinedwith an agent that inhibits infection.

7803. The method of item 7730, wherein the implant is further combinedwith an anthracycline.

7804. The method of item 7730, wherein the implant is further combinedwith doxorubicin.

7805. The method of item 7730, wherein the implant is further combinedwith mitoxantrone.

7806. The method of item 7730, wherein the implant is further combinedwith a fluoropyrimidine.

7807. The method of item 7730, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

7808. The method of item 7730, wherein the implant is further combinedwith a folic acid antagonist.

7809. The method of item 7730, wherein the implant is further combinedwith methotrexate.

7810. The method of item 7730, wherein the implant is further combinedwith a podophylotoxin.

7811. The method of item 7730, wherein the implant is further combinedwith etoposide.

7812. The method of item 7730 wherein the implant is further combinedwith a camptothecin.

7813. The method of item 7730, wherein the implant is further combinedwith a hydroxyurea.

7814. The method of item 7730, wherein the implant is further combinedwith a platinum complex.

7815. The method of item 7730, wherein the implant is further combinedwith cisplatin.

7816. The method of item 7730, wherein the implant is further combinedwith an anti-thrombotic agent.

7817. The method of item 7730, wherein the implant is further combinedwith a visualization agent.

7818. The method of item 7730, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

7819. The method of item 7730, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

7820. The method of item 7730, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

7821. The method of item 7730, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

7822. The method of item 7730, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

7823. The method of item 7730, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

7824. The method of item 7730, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

7825. The method of item 7730, wherein the implant is further combinedwith an echogenic material.

7826. The method of item 7730, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

7827. The method of item 7730 wherein the device is sterilized.

7828. The method of item 7730 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

7829. The method of item 7730 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

7830. The method of item 7730 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

7831. The method of item 7730 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

7832. The method of item 7730 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

7833. The method of item 7730 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

7834. The method of item 7730 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

7835. The method of item 7730 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

7836. The method of item 7730 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

7837. The method of item 7730 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

7838. The method of item 7730 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

7839. The method of item 7730 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

7840. The method of item 7730 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

7841. The method of item 7730 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

7842. The method of item 7730 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

7843. The method of item 7730 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

7844. The method of item 7730 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

7845. The method of item 7730 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

7846. The method of item 7730 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

7847. The method of item 7730 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7848. The method of item 7730 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7849. The method of item 7730 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7850. The method of item 7730 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

7851. The method of item 7730 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7852. The method of item 7730 wherein the implant is a titanium fixturefor replacement of the root portion of a missing natural tooth.

7853. The method of item 7730 wherein the implant is an endostealimplant.

7854. The method of item 7730 wherein the implant is an subperiostealimplant.

7855. The method of item 7730 wherein the implant is a guided boneregeneration (GBR) implant.

7856. The method of item 7730 wherein the implant is a dental implantthat controls the healing process subsequent to periodontal disease.

7857. A method of making a medical device comprising combining i) aninternal fixation implant and ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

7858. The method of item 7857 wherein the fibrosing agent promotesregeneration.

7859. The method of item 7857 wherein the fibrosing agent promotesangiogenesis.

7860. The method of item 7857 wherein the fibrosing agent promotesfibroblast migration.

7861. The method of item 7857 wherein the fibrosing agent promotesfibroblast proliferation.

7862. The method of item 7857 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

7863. The method of item 7857 wherein the fibrosing agent promotestissue remodeling.

7864. The method of item 7857 wherein the fibrosing agent is an arterialvessel wall irritant.

7865. The method of item 7857 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7866. The method of item 7857 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7867. The method of item 7857 wherein the fibrosing agent is orcomprises silk.

7868. The method of item 7857 wherein the fibrosing agent is orcomprises mineral particles.

7869. The method of item 7857 wherein the fibrosing agent is orcomprises chitosan.

7870. The method of item 7857 wherein the fibrosing agent is orcomprises polylysine.

7871. The method of item 7857 wherein the fibrosing agent is orcomprises fibronectin.

7872. The method of item 7857 wherein the fibrosing agent is orcomprises bleomycin.

7873. The method of item 7857 wherein the fibrosing agent is orcomprises CTGF.

7874. The method of item 7857 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

7875. The method of item 7857 wherein the fibrosing agent is in the formof a particulate.

7876. The method of item 7857 wherein the composition further comprisesan inflammatory cytokine.

7877. The method of item 7857 wherein the composition further comprisesan agent that stimulates cell proliferation.

7878. The method of item 7857 wherein the composition is in the form ofa gel or paste.

7879. The method of item 7857 wherein the fibrosing agent is in the formof tufts.

7880. The method of item 7857 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

7881. The method of item 7857 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

7882. The method of item 7857, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

7883. The method of item 7857, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

7884. The method of item 7857, wherein the implant is combined with acoating, and the coating directly contacts the device.

7885. The method of item 7857, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

7886. The method of item 7857, wherein the implant is combined with acoating, and the coating partially covers the device.

7887. The method of item 7857, wherein the implant is combined with acoating, and the coating completely covers the device.

7888. The method of item 7857, wherein the implant is combined with acoating, and the coating is a uniform coating.

7889. The method of item 7857, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

7890. The method of item 7857, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

7891. The method of item 7857 wherein the implant is combined with acoating, and the coating is a patterned coating.

7892. The method of item 7857, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

7893. The method of item 7857, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

7894. The method of item 7857, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

7895. The method of item 7857, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

7896. The method of item 7857, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

7897. The method of item 7857, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

7898. The method of item 7857, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

7899. The method of item 7857, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

7900. The method of item 7857, wherein the implant is combined with acoating, and the coating further comprises a polymer.

7901. The method of item 7857, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

7902. The method of item 7857, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

7903. The method of item 7857, wherein the device comprises a polymer.

7904. The method of item 7857, wherein the device comprises a polymer,and the polymer is a component of the composition.

7905. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a copolymer.

7906. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

7907. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

7908. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

7909. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

7910. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

7911. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

7912. The method of item 7857, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

7913. The method of item 7857, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

7914. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

7915. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is an elastomer.

7916. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

7917. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

7918. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

7919. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

7920. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

7921. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a macromer.

7922. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

7923. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

7924. The method of item 7857, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

7925. The method of item 7857 wherein the fibrosing agent is locatedwithin pores or holes of the device.

7926. The method of item 7857 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

7927. The method of item 7857, wherein the implant is further combinedwith a second pharmaceutically active agent.

7928. The method of item 7857, wherein the implant is further combinedwith an anti-inflammatory agent.

7929. The method of item 7857 wherein the implant is further combinedwith an agent that inhibits infection.

7930. The method of item 7857, wherein the implant is further combinedwith an anthracycline.

7931. The method of item 7857, wherein the implant is further combinedwith doxorubicin.

7932. The method of item 7857, wherein the implant is further combinedwith mitoxantrone.

7933. The method of item 7857, wherein the implant is further combinedwith a fluoropyrimidine.

7934. The method of item 7857, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

7935. The method of item 7857, wherein the implant is further combinedwith a folic acid antagonist.

7936. The method of item 7857, wherein the implant is further combinedwith methotrexate.

7937. The method of item 7857, wherein the implant is further combinedwith a podophylotoxin.

7938. The method of item 7857, wherein the implant is further combinedwith etoposide.

7939. The method of item 7857 wherein the implant is further combinedwith a camptothecin.

7940. The method of item 7857, wherein the implant is further combinedwith a hydroxyurea.

7941. The method of item 7857, wherein the implant is further combinedwith a platinum complex.

7942. The method of item 7857, wherein the implant is further combinedwith cisplatin.

7943. The method of item 7857, wherein the implant is further combinedwith an anti-thrombotic agent.

7944. The method of item 7857, wherein the implant is further combinedwith a visualization agent.

7945. The method of item 7857, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

7946. The method of item 7857, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

7947. The method of item 7857, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

7948. The method of item 7857, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

7949. The method of item 7857, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

7950. The method of item 7857, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

7951. The method of item 7857, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

7952. The method of item 7857, wherein the implant is further combinedwith an echogenic material.

7953. The method of item 7857, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

7954. The method of item 7857 wherein the device is sterilized.

7955. The method of item 7857 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

7956. The method of item 7857 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

7957. The method of item 7857 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

7958. The method of item 7857 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

7959. The method of item 7857 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

7960. The method of item 7857 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

7961. The method of item 7857 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

7962. The method of item 7857 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

7963. The method of item 7857 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

7964. The method of item 7857 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

7965. The method of item 7857 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

7966. The method of item 7857 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

7967. The method of item 7857 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

7968. The method of item 7857 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

7969. The method of item 7857 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

7970. The method of item 7857 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

7971. The method of item 7857 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

7972. The method of item 7857 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

7973. The method of item 7857 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

7974. The method of item 7857 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7975. The method of item 7857 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7976. The method of item 7857 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7977. The method of item 7857 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

7978. The method of item 7857 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

7979. The method of item 7857 wherein the implant comprises a screw.

7980. The method of item 7857 wherein the implant is, or comprises, afixation screw.

7981. The method of item 7857 wherein the implant is, or comprises, aninterferential screw.

7982. The method of item 7857 wherein the implant is, or comprises, atrochanteric screw.

7983. The method of item 7857 wherein the implant comprises a pin.

7984. The method of item 7857 wherein the implant comprises a sideplate.

7985. The method of item 7857 wherein the implant is an intramedullarynail.

7986. The method of item 7857 wherein the implant is an intramedullarypin.

7987. The method of item 7857 wherein the implant is a bone plate.

7988. The method of item 7857 wherein the implant is bone screw.

7989. The method of item 7857 wherein the implant is a smooth pin.

7990. The method of item 7857 wherein the implant is a threaded pin.

7991. The method of item 7857 wherein the implant is a wire.

7992. The method of item 7857 wherein the implant is a plate.

7993. A method of making a medical device comprising combining i) anexternal fixation implant and ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

7994. The method of item 7993 wherein the fibrosing agent promotesregeneration.

7995. The method of item 7993 wherein the fibrosing agent promotesangiogenesis.

7996. The method of item 7993 wherein the fibrosing agent promotesfibroblast migration.

7997. The method of item 7993 wherein the fibrosing agent promotesfibroblast proliferation.

7998. The method of item 7993 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

7999. The method of item 7993 wherein the fibrosing agent promotestissue remodeling.

8000. The method of item 7993 wherein the fibrosing agent is an arterialvessel wall irritant.

8001. The method of item 7993 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8002. The method of item 7993 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8003. The method of item 7993 wherein the fibrosing agent is orcomprises silk.

8004. The method of item 7993 wherein the fibrosing agent is orcomprises mineral particles.

8005. The method of item 7993 wherein the fibrosing agent is orcomprises chitosan.

8006. The method of item 7993 wherein the fibrosing agent is orcomprises polylysine.

8007. The method of item 7993 wherein the fibrosing agent is orcomprises fibronectin.

8008. The method of item 7993 wherein the fibrosing agent is orcomprises bleomycin.

8009. The method of item 7993 wherein the fibrosing agent is orcomprises CTGF.

8010. The method of item 7993 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

8011. The method of item 7993 wherein the fibrosing agent is in the formof a particulate.

8012. The method of item 7993 wherein the composition further comprisesan inflammatory cytokine.

8013. The method of item 7993 wherein the composition further comprisesan agent that stimulates cell proliferation.

8014. The method of item 7993 wherein the composition is in the form ofa gel or paste.

8015. The method of item 7993 wherein the fibrosing agent is in the formof tufts.

8016. The method of item 7993 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8017. The method of item 7993 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8018. The method of item 7993, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

8019. The method of item 7993, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

8020. The method of item 7993, wherein the implant is combined with acoating, and the coating directly contacts the device.

8021. The method of item 7993, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

8022. The method of item 7993, wherein the implant is combined with acoating, and the coating partially covers the device.

8023. The method of item 7993, wherein the implant is combined with acoating, and the coating completely covers the device.

8024. The method of item 7993, wherein the implant is combined with acoating, and the coating is a uniform coating.

8025. The method of item 7993, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

8026. The method of item 7993, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

8027. The method of item 7993 wherein the implant is combined with acoating, and the coating is a patterned coating.

8028. The method of item 7993, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

8029. The method of item 7993, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

8030. The method of item 7993, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

8031. The method of item 7993, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

8032. The method of item 7993, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

8033. The method of item 7993, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

8034. The method of item 7993, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

8035. The method of item 7993, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

8036. The method of item 7993, wherein the implant is combined with acoating, and the coating further comprises a polymer.

8037. The method of item 7993, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

8038. The method of item 7993, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

8039. The method of item 7993, wherein the device comprises a polymer.

8040. The method of item 7993, wherein the device comprises a polymer,and the polymer is a component of the composition.

8041. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a copolymer.

8042. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

8043. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

8044. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

8045. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

8046. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

8047. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

8048. The method of item 7993, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

8049. The method of item 7993, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

8050. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

8051. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is an elastomer.

8052. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

8053. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

8054. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

8055. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

8056. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

8057. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a macromer.

8058. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

8059. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

8060. The method of item 7993, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

8061. The method of item 7993 wherein the fibrosing agent is locatedwithin pores or holes of the device.

8062. The method of item 7993 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

8063. The method of item 7993, wherein the implant is further combinedwith a second pharmaceutically active agent.

8064. The method of item 7993, wherein the implant is further combinedwith an anti-inflammatory agent.

8065. The method of item 7993 wherein the implant is further combinedwith an agent that inhibits infection.

8066. The method of item 7993, wherein the implant is further combinedwith an anthracycline.

8067. The method of item 7993, wherein the implant is further combinedwith doxorubicin.

8068. The method of item 7993, wherein the implant is further combinedwith mitoxantrone.

8069. The method of item 7993, wherein the implant is further combinedwith a fluoropyrimidine.

8070. The method of item 7993, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

8071. The method of item 7993, wherein the implant is further combinedwith a folic acid antagonist.

8072. The method of item 7993, wherein the implant is further combinedwith methotrexate.

8073. The method of item 7993, wherein the implant is further combinedwith a podophylotoxin.

8074. The method of item 7993, wherein the implant is further combinedwith etoposide.

8075. The method of item 7993 wherein the implant is further combinedwith a camptothecin.

8076. The method of item 7993, wherein the implant is further combinedwith a hydroxyurea.

8077. The method of item 7993, wherein the implant is further combinedwith a platinum complex.

8078. The method of item 7993, wherein the implant is further combinedwith cisplatin.

8079. The method of item 7993, wherein the implant is further combinedwith an anti-thrombotic agent.

8080. The method of item 7993, wherein the implant is further combinedwith a visualization agent.

8081. The method of item 7993, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

8082. The method of item 7993, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

8083. The method of item 7993, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

8084. The method of item 7993, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

8085. The method of item 7993, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

8086. The method of item 7993, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

8087. The method of item 7993, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

8088. The method of item 7993, wherein the implant is further combinedwith an echogenic material.

8089. The method of item 7993, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

8090. The method of item 7993 wherein the device is sterilized.

8091. The method of item 7993 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

8092. The method of item 7993 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

8093. The method of item 7993 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

8094. The method of item 7993 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

8095. The method of item 7993 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

8096. The method of item 7993 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

8097. The method of item 7993 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

8098. The method of item 7993 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

8099. The method of item 7993 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

8100. The method of item 7993 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

8101. The method of item 7993 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

8102. The method of item 7993 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

8103. The method of item 7993 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

8104. The method of item 7993 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

8105. The method of item 7993 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

8106. The method of item 7993 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

8107. The method of item 7993 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

8108. The method of item 7993 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

8109. The method of item 7993 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

8110. The method of item 7993 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8111. The method of item 7993 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8112. The method of item 7993 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8113. The method of item 7993 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

8114. The method of item 7993 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8115. The method of item 7993 wherein the implant is in the form of apin.

8116. The method of item 7993 wherein the implant is used to stabilizetransverse fractures.

8117. The method of item 7993 wherein the implant comprises steel.

8118. A method of making a medical device comprising combining i) acollagen implant and ii) a fibrosing agent or a composition comprising afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

8119. The method of item 8118 wherein the fibrosing agent promotesregeneration.

8120. The method of item 8118 wherein the fibrosing agent promotesangiogenesis.

8121. The method of item 8118 wherein the fibrosing agent promotesfibroblast migration.

8122. The method of item 8118 wherein the fibrosing agent promotesfibroblast proliferation.

8123. The method of item 8118 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

8124. The method of item 8118 wherein the fibrosing agent promotestissue remodeling.

8125. The method of item 8118 wherein the fibrosing agent is an arterialvessel wall irritant.

8126. The method of item 8118 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8127. The method of item 8118 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8128. The method of item 8118 wherein the fibrosing agent is orcomprises silk.

8129. The method of item 8118 wherein the fibrosing agent is orcomprises mineral particles.

8130. The method of item 8118 wherein the fibrosing agent is orcomprises chitosan.

8131. The method of item 8118 wherein the fibrosing agent is orcomprises polylysine.

8132. The method of item 8118 wherein the fibrosing agent is orcomprises fibronectin.

8133. The method of item 8118 wherein the fibrosing agent is orcomprises bleomycin.

8134. The method of item 8118 wherein the fibrosing agent is orcomprises CTGF.

8135. The method of item 8118 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

8136. The method of item 8118 wherein the fibrosing agent is in the formof a particulate.

8137. The method of item 8118 wherein the composition further comprisesan inflammatory cytokine.

8138. The method of item 8118 wherein the composition further comprisesan agent that stimulates cell proliferation.

8139. The method of item 8118 wherein the composition is in the form ofa gel or paste.

8140. The method of item 8118 wherein the fibrosing agent is in the formof tufts.

8141. The method of item 8118 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8142. The method of item 8118 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8143. The method of item 8118, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

8144. The method of item 8118, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

8145. The method of item 8118, wherein the implant is combined with acoating, and the coating directly contacts the device.

8146. The method of item 8118, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

8147. The method of item 8118, wherein the implant is combined with acoating, and the coating partially covers the device.

8148. The method of item 8118, wherein the implant is combined with acoating, and the coating completely covers the device.

8149. The method of item 8118, wherein the implant is combined with acoating, and the coating is a uniform coating.

8150. The method of item 8118, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

8151. The method of item 8118, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

8152. The method of item 8118 wherein the implant is combined with acoating, and the coating is a patterned coating.

8153. The method of item 8118, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

8154. The method of item 8118, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

8155. The method of item 8118, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

8156. The method of item 8118, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

8157. The method of item 8118, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

8158. The method of item 8118, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

8159. The method of item 8118, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

8160. The method of item 8118, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

8161. The method of item 8118, wherein the implant is combined with acoating, and the coating further comprises a polymer.

8162. The method of item 8118, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

8163. The method of item 8118, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

8164. The method of item 8118, wherein the device comprises a polymer.

8165. The method of item 8118, wherein the device comprises a polymer,and the polymer is a component of the composition.

8166. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a copolymer.

8167. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

8168. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

8169. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

8170. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

8171. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

8172. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

8173. The method of item 8118, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

8174. The method of item 8118, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

8175. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

8176. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is an elastomer.

8177. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

8178. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

8179. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

8180. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

8181. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

8182. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a macromer.

8183. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

8184. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

8185. The method of item 8118, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

8186. The method of item 8118 wherein the fibrosing agent is locatedwithin pores or holes of the device.

8187. The method of item 8118 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

8188. The method of item 8118, wherein the implant is further combinedwith a second pharmaceutically active agent.

8189. The method of item 8118, wherein the implant is further combinedwith an anti-inflammatory agent.

8190. The method of item 8118 wherein the implant is further combinedwith an agent that inhibits infection.

8191. The method of item 8118, wherein the implant is further combinedwith an anthracycline.

8192. The method of item 8118, wherein the implant is further combinedwith doxorubicin.

8193. The method of item 8118, wherein the implant is further combinedwith mitoxantrone.

8194. The method of item 8118, wherein the implant is further combinedwith a fluoropyrimidine.

8195. The method of item 8118, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

8196. The method of item 8118, wherein the implant is further combinedwith a folic acid antagonist.

8197. The method of item 8118, wherein the implant is further combinedwith methotrexate.

8198. The method of item 8118, wherein the implant is further combinedwith a podophylotoxin.

8199. The method of item 8118, wherein the implant is further combinedwith etoposide.

8200. The method of item 8118 wherein the implant is further combinedwith a camptothecin.

8201. The method of item 8118, wherein the implant is further combinedwith a hydroxyurea.

8202. The method of item 8118, wherein the implant is further combinedwith a platinum complex.

8203. The method of item 8118, wherein the implant is further combinedwith cisplatin.

8204. The method of item 8118, wherein the implant is further combinedwith an anti-thrombotic agent.

8205. The method of item 8118, wherein the implant is further combinedwith a visualization agent.

8206. The method of item 8118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

8207. The method of item 8118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

8208. The method of item 8118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

8209. The method of item 8118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

8210. The method of item 8118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

8211. The method of item 8118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

8212. The method of item 8118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

8213. The method of item 8118, wherein the implant is further combinedwith an echogenic material.

8214. The method of item 8118, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

8215. The method of item 8118 wherein the device is sterilized.

8216. The method of item 8118 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

8217. The method of item 8118 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

8218. The method of item 8118 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

8219. The method of item 8118 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

8220. The method of item 8118 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

8221. The method of item 8118 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

8222. The method of item 8118 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

8223. The method of item 8118 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

8224. The method of item 8118 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

8225. The method of item 8118 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

8226. The method of item 8118 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

8227. The method of item 8118 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

8228. The method of item 8118 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

8229. The method of item 8118 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

8230. The method of item 8118 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

8231. The method of item 8118 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

8232. The method of item 8118 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

8233. The method of item 8118 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

8234. The method of item 8118 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

8235. The method of item 8118 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8236. The method of item 8118 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8237. The method of item 8118 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8238. The method of item 8118 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

8239. The method of item 8118 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8240. The method of item 8118 wherein the implant is a dental implant.

8241. The method of item 8118 wherein the implant is an orthopedicimplant.

8242. The method of item 8118 wherein the implant is a surgical mesh.

8243. The method of item 8118 wherein the implant is made, in whole orpart, from crosslinked collagen.

8244. A method of making a medical device comprising combining i) aFallopian tube implant and ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

8245. The method of item 8244 wherein the fibrosing agent promotesregeneration.

8246. The method of item 8244 wherein the fibrosing agent promotesangiogenesis.

8247. The method of item 8244 wherein the fibrosing agent promotesfibroblast migration.

8248. The method of item 8244 wherein the fibrosing agent promotesfibroblast proliferation.

8249. The method of item 8244 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

8250. The method of item 8244 wherein the fibrosing agent promotestissue remodeling.

8251. The method of item 8244 wherein the fibrosing agent is an arterialvessel wall irritant.

8252. The method of item 8244 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8253. The method of item 8244 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8254. The method of item 8244 wherein the fibrosing agent is orcomprises silk.

8255. The method of item 8244 wherein the fibrosing agent is orcomprises mineral particles.

8256. The method of item 8244 wherein the fibrosing agent is orcomprises chitosan.

8257. The method of item 8244 wherein the fibrosing agent is orcomprises polylysine.

8258. The method of item 8244 wherein the fibrosing agent is orcomprises fibronectin.

8259. The method of item 8244 wherein the fibrosing agent is orcomprises bleomycin.

8260. The method of item 8244 wherein the fibrosing agent is orcomprises CTGF.

8261. The method of item 8244 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

8262. The method of item 8244 wherein the fibrosing agent is in the formof a particulate.

8263. The method of item 8244 wherein the composition further comprisesan inflammatory cytokine.

8264. The method of item 8244 wherein the composition further comprisesan agent that stimulates cell proliferation.

8265. The method of item 8244 wherein the composition is in the form ofa gel or paste.

8266. The method of item 8244 wherein the fibrosing agent is in the formof tufts.

8267. The method of item 8244 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8268. The method of item 8244 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8269. The method of item 8244, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

8270. The method of item 8244, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

8271. The method of item 8244, wherein the implant is combined with acoating, and the coating directly contacts the device.

8272. The method of item 8244, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

8273. The method of item 8244, wherein the implant is combined with acoating, and the coating partially covers the device.

8274. The method of item 8244, wherein the implant is combined with acoating, and the coating completely covers the device.

8275. The method of item 8244, wherein the implant is combined with acoating, and the coating is a uniform coating.

8276. The method of item 8244, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

8277. The method of item 8244, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

8278. The method of item 8244 wherein the implant is combined with acoating, and the coating is a patterned coating.

8279. The method of item 8244, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

8280. The method of item 8244, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

8281. The method of item 8244, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

8282. The method of item 8244, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

8283. The method of item 8244, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

8284. The method of item 8244, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

8285. The method of item 8244, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

8286. The method of item 8244, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

8287. The method of item 8244, wherein the implant is combined with acoating, and the coating further comprises a polymer.

8288. The method of item 8244, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

8289. The method of item 8244, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

8290. The method of item 8244, wherein the device comprises a polymer.

8291. The method of item 8244, wherein the device comprises a polymer,and the polymer is a component of the composition.

8292. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a copolymer.

8293. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

8294. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

8295. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

8296. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

8297. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

8298. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

8299. The method of item 8244, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

8300. The method of item 8244, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

8301. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

8302. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is an elastomer.

8303. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

8304. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

8305. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

8306. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

8307. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

8308. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a macromer.

8309. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

8310. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

8311. The method of item 8244, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

8312. The method of item 8244 wherein the fibrosing agent is locatedwithin pores or holes of the device.

8313. The method of item 8244 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

8314. The method of item 8244, wherein the implant is further combinedwith a second pharmaceutically active agent.

8315. The method of item 8244, wherein the implant is further combinedwith an anti-inflammatory agent.

8316. The method of item 8244 wherein the implant is further combinedwith an agent that inhibits infection.

8317. The method of item 8244, wherein the implant is further combinedwith an anthracycline.

8318. The method of item 8244, wherein the implant is further combinedwith doxorubicin.

8319. The method of item 8244, wherein the implant is further combinedwith mitoxantrone.

8320. The method of item 8244, wherein the implant is further combinedwith a fluoropyrimidine.

8321. The method of item 8244, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

8322. The method of item 8244, wherein the implant is further combinedwith a folic acid antagonist.

8323. The method of item 8244, wherein the implant is further combinedwith methotrexate.

8324. The method of item 8244, wherein the implant is further combinedwith a podophylotoxin.

8325. The method of item 8244, wherein the implant is further combinedwith etoposide.

8326. The method of item 8244 wherein the implant is further combinedwith a camptothecin.

8327. The method of item 8244, wherein the implant is further combinedwith a hydroxyurea.

8328. The method of item 8244, wherein the implant is further combinedwith a platinum complex.

8329. The method of item 8244, wherein the implant is further combinedwith cisplatin.

8330. The method of item 8244, wherein the implant is further combinedwith an anti-thrombotic agent.

8331. The method of item 8244, wherein the implant is further combinedwith a visualization agent.

8332. The method of item 8244, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

8333. The method of item 8244, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

8334. The method of item 8244, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

8335. The method of item 8244, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

8336. The method of item 8244, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

8337. The method of item 8244, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

8338. The method of item 8244, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

8339. The method of item 8244, wherein the implant is further combinedwith an echogenic material.

8340. The method of item 8244, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

8341. The method of item 8244 wherein the device is sterilized.

8342. The method of item 8244 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

8343. The method of item 8244 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

8344. The method of item 8244 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

8345. The method of item 8244 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

8346. The method of item 8244 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

8347. The method of item 8244 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

8348. The method of item 8244 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

8349. The method of item 8244 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

8350. The method of item 8244 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

8351. The method of item 8244 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

8352. The method of item 8244 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

8353. The method of item 8244 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

8354. The method of item 8244 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

8355. The method of item 8244 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

8356. The method of item 8244 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

8357. The method of item 8244 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

8358. The method of item 8244 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

8359. The method of item 8244 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

8360. The method of item 8244 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

8361. The method of item 8244 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8362. The method of item 8244 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8363. The method of item 8244 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8364. The method of item 8244 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

8365. The method of item 8244 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8366. The method of item 8244 wherein the implant is a duct clamp.

8367. The method of item 8244 wherein the implant is a valvedsterilization device.

8368. The method of item 8244 wherein the implant is an implantable,intrafallopian, female sterilization device.

8369. The method of item 8244 wherein the implant is an occlusive wireor coil fallopian tube implant.

8370. The method of item 8244 wherein the implant is a transcatheteroccluding implant.

8371. The method of item 8244 wherein the implant is a fallopian tubestent.

8372. The method of item 8244 wherein the implant is a contraceptiveuterine implant.

8373. A method of making a medical device comprising combining i) aprosthetic anal sphincter and ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

8374. The method of item 8373 wherein the fibrosing agent promotesregeneration.

8375. The method of item 8373 wherein the fibrosing agent promotesangiogenesis.

8376. The method of item 8373 wherein the fibrosing agent promotesfibroblast migration.

8377. The method of item 8373 wherein the fibrosing agent promotesfibroblast proliferation.

8378. The method of item 8373 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

8379. The method of item 8373 wherein the fibrosing agent promotestissue remodeling.

8380. The method of item 8373 wherein the fibrosing agent is an arterialvessel wall irritant.

8381. The method of item 8373 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8382. The method of item 8373 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8383. The method of item 8373 wherein the fibrosing agent is orcomprises silk.

8384. The method of item 8373 wherein the fibrosing agent is orcomprises mineral particles.

8385. The method of item 8373 wherein the fibrosing agent is orcomprises chitosan.

8386. The method of item 8373 wherein the fibrosing agent is orcomprises polylysine.

8387. The method of item 8373 wherein the fibrosing agent is orcomprises fibronectin.

8388. The method of item 8373 wherein the fibrosing agent is orcomprises bleomycin.

8389. The method of item 8373 wherein the fibrosing agent is orcomprises CTGF.

8390. The method of item 8373 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

8391. The method of item 8373 wherein the fibrosing agent is in the formof a particulate.

8392. The method of item 8373 wherein the composition further comprisesan inflammatory cytokine.

8393. The method of item 8373 wherein the composition further comprisesan agent that stimulates cell proliferation.

8394. The method of item 8373 wherein the composition is in the form ofa gel or paste.

8395. The method of item 8373 wherein the fibrosing agent is in the formof tufts.

8396. The method of item 8373 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8397. The method of item 8373 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8398. The method of item 8373, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

8399. The method of item 8373, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

8400. The method of item 8373, wherein the implant is combined with acoating, and the coating directly contacts the device.

8401. The method of item 8373, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

8402. The method of item 8373, wherein the implant is combined with acoating, and the coating partially covers the device.

8403. The method of item 8373, wherein the implant is combined with acoating, and the coating completely covers the device.

8404. The method of item 8373, wherein the implant is combined with acoating, and the coating is a uniform coating.

8405. The method of item 8373, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

8406. The method of item 8373, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

8407. The method of item 8373 wherein the implant is combined with acoating, and the coating is a patterned coating.

8408. The method of item 8373, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

8409. The method of item 8373, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

8410. The method of item 8373, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

8411. The method of item 8373, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

8412. The method of item 8373, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

8413. The method of item 8373, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

8414. The method of item 8373, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

8415. The method of item 8373, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

8416. The method of item 8373, wherein the implant is combined with acoating, and the coating further comprises a polymer.

8417. The method of item 8373, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

8418. The method of item 8373, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

8419. The method of item 8373, wherein the device comprises a polymer.

8420. The method of item 8373, wherein the device comprises a polymer,and the polymer is a component of the composition.

8421. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a copolymer.

8422. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

8423. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

8424. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

8425. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

8426. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

8427. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

8428. The method of item 8373, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

8429. The method of item 8373, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

8430. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

8431. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is an elastomer.

8432. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

8433. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

8434. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

8435. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

8436. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

8437. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a macromer.

8438. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

8439. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

8440. The method of item 8373, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

8441. The method of item 8373 wherein the fibrosing agent is locatedwithin pores or holes of the device.

8442. The method of item 8373 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

8443. The method of item 8373, wherein the implant is further combinedwith a second pharmaceutically active agent.

8444. The method of item 8373, wherein the implant is further combinedwith an anti-inflammatory agent.

8445. The method of item 8373 wherein the implant is further combinedwith an agent that inhibits infection.

8446. The method of item 8373, wherein the implant is further combinedwith an anthracycline.

8447. The method of item 8373, wherein the implant is further combinedwith doxorubicin.

8448. The method of item 8373, wherein the implant is further combinedwith mitoxantrone.

8449. The method of item 8373, wherein the implant is further combinedwith a fluoropyrimidine.

8450. The method of item 8373, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

8451. The method of item 8373, wherein the implant is further combinedwith a folic acid antagonist.

8452. The method of item 8373, wherein the implant is further combinedwith methotrexate.

8453. The method of item 8373, wherein the implant is further combinedwith a podophylotoxin.

8454. The method of item 8373, wherein the implant is further combinedwith etoposide.

8455. The method of item 8373 wherein the implant is further combinedwith a camptothecin.

8456. The method of item 8373, wherein the implant is further combinedwith a hydroxyurea.

8457. The method of item 8373, wherein the implant is further combinedwith a platinum complex.

8458. The method of item 8373, wherein the implant is further combinedwith cisplatin.

8459. The method of item 8373, wherein the implant is further combinedwith an anti-thrombotic agent.

8460. The method of item 8373, wherein the implant is further combinedwith a visualization agent.

8461. The method of item 8373, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

8462. The method of item 8373, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

8463. The method of item 8373, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

8464. The method of item 8373, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

8465. The method of item 8373, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

8466. The method of item 8373, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

8467. The method of item 8373, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

8468. The method of item 8373, wherein the implant is further combinedwith an echogenic material.

8469. The method of item 8373, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

8470. The method of item 8373 wherein the device is sterilized.

8471. The method of item 8373 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

8472. The method of item 8373 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

8473. The method of item 8373 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

8474. The method of item 8373 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

8475. The method of item 8373 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

8476. The method of item 8373 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

8477. The method of item 8373 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

8478. The method of item 8373 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

8479. The method of item 8373 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

8480. The method of item 8373 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

8481. The method of item 8373 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

8482. The method of item 8373 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

8483. The method of item 8373 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

8484. The method of item 8373 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

8485. The method of item 8373 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

8486. The method of item 8373 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

8487. The method of item 8373 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

8488. The method of item 8373 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

8489. The method of item 8373 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

8490. The method of item 8373 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8491. The method of item 8373 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8492. The method of item 8373 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8493. The method of item 8373 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

8494. The method of item 8373 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8495. The method of item 8373 wherein the implant is, or comprises, anablation device.

8496. The method of item 8373 wherein the implant is, or comprises, anerve stimulator.

8497. The method of item 8373 wherein the implant is, or comprises, apump.

8498. The method of item 8373 wherein the implant is, or comprises, astapling device.

8499. A method of making a medical device comprising combining i) animplantable male contraceptive device and ii) a fibrosing agent or acomposition comprising a fibrosing agent, where the fibrosing agentinduces a fibrotic response between the device and a patient in whichthe device is implanted.

8500. The method of item 8499 wherein the fibrosing agent promotesregeneration.

8501. The method of item 8499 wherein the fibrosing agent promotesangiogenesis.

8502. The method of item 8499 wherein the fibrosing agent promotesfibroblast migration.

8503. The method of item 8499 wherein the fibrosing agent promotesfibroblast proliferation.

8504. The method of item 8499 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

8505. The method of item 8499 wherein the fibrosing agent promotestissue remodeling.

8506. The method of item 8499 wherein the fibrosing agent is an arterialvessel wall irritant.

8507. The method of item 8499 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8508. The method of item 8499 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8509. The method of item 8499 wherein the fibrosing agent is orcomprises silk.

8510. The method of item 8499 wherein the fibrosing agent is orcomprises mineral particles.

8511. The method of item 8499 wherein the fibrosing agent is orcomprises chitosan.

8512. The method of item 8499 wherein the fibrosing agent is orcomprises polylysine.

8513. The method of item 8499 wherein the fibrosing agent is orcomprises fibronectin.

8514. The method of item 8499 wherein the fibrosing agent is orcomprises bleomycin.

8515. The method of item 8499 wherein the fibrosing agent is orcomprises CTGF.

8516. The method of item 8499 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

8517. The method of item 8499 wherein the fibrosing agent is in the formof a particulate.

8518. The method of item 8499 wherein the composition further comprisesan inflammatory cytokine.

8519. The method of item 8499 wherein the composition further comprisesan agent that stimulates cell proliferation.

8520. The method of item 8499 wherein the composition is in the form ofa gel or paste.

8521. The method of item 8499 wherein the fibrosing agent is in the formof tufts.

8522. The method of item 8499 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8523. The method of item 8499 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8524. The method of item 8499, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

8525. The method of item 8499, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

8526. The method of item 8499, wherein the implant is combined with acoating, and the coating directly contacts the device.

8527. The method of item 8499, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

8528. The method of item 8499, wherein the implant is combined with acoating, and the coating partially covers the device.

8529. The method of item 8499, wherein the implant is combined with acoating, and the coating completely covers the device.

8530. The method of item 8499, wherein the implant is combined with acoating, and the coating is a uniform coating.

8531. The method of item 8499, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

8532. The method of item 8499, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

8533. The method of item 8499 wherein the implant is combined with acoating, and the coating is a patterned coating.

8534. The method of item 8499, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

8535. The method of item 8499, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

8536. The method of item 8499, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

8537. The method of item 8499, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

8538. The method of item 8499, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

8539. The method of item 8499, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

8540. The method of item 8499, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

8541. The method of item 8499, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

8542. The method of item 8499, wherein the implant is combined with acoating, and the coating further comprises a polymer.

8543. The method of item 8499, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

8544. The method of item 8499, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

8545. The method of item 8499, wherein the device comprises a polymer.

8546. The method of item 8499, wherein the device comprises a polymer,and the polymer is a component of the composition.

8547. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a copolymer.

8548. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

8549. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

8550. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

8551. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

8552. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

8553. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

8554. The method of item 8499, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

8555. The method of item 8499, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

8556. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

8557. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is an elastomer.

8558. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

8559. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

8560. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

8561. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

8562. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

8563. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a macromer.

8564. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

8565. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

8566. The method of item 8499, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

8567. The method of item 8499 wherein the fibrosing agent is locatedwithin pores or holes of the device.

8568. The method of item 8499 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

8569. The method of item 8499, wherein the implant is further combinedwith a second pharmaceutically active agent.

8570. The method of item 8499, wherein the implant is further combinedwith an anti-inflammatory agent.

8571. The method of item 8499 wherein the implant is further combinedwith an agent that inhibits infection.

8572. The method of item 8499, wherein the implant is further combinedwith an anthracycline.

8573. The method of item 8499, wherein the implant is further combinedwith doxorubicin.

8574. The method of item 8499, wherein the implant is further combinedwith mitoxantrone.

8575. The method of item 8499, wherein the implant is further combinedwith a fluoropyrimidine.

8576. The method of item 8499, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

8577. The method of item 8499, wherein the implant is further combinedwith a folic acid antagonist.

8578. The method of item 8499, wherein the implant is further combinedwith methotrexate.

8579. The method of item 8499, wherein the implant is further combinedwith a podophylotoxin.

8580. The method of item 8499, wherein the implant is further combinedwith etoposide.

8581. The method of item 8499 wherein the implant is further combinedwith a camptothecin.

8582. The method of item 8499, wherein the implant is further combinedwith a hydroxyurea.

8583. The method of item 8499, wherein the implant is further combinedwith a platinum complex.

8584. The method of item 8499, wherein the implant is further combinedwith cisplatin.

8585. The method of item 8499, wherein the implant is further combinedwith an anti-thrombotic agent.

8586. The method of item 8499, wherein the implant is further combinedwith a visualization agent.

8587. The method of item 8499, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

8588. The method of item 8499, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

8589. The method of item 8499, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

8590. The method of item 8499, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

8591. The method of item 8499, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

8592. The method of item 8499, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

8593. The method of item 8499, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

8594. The method of item 8499, wherein the implant is further combinedwith an echogenic material.

8595. The method of item 8499, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

8596. The method of item 8499 wherein the device is sterilized.

8597. The method of item 8499 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

8598. The method of item 8499 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

8599. The method of item 8499 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

8600. The method of item 8499 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

8601. The method of item 8499 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

8602. The method of item 8499 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

8603. The method of item 8499 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

8604. The method of item 8499 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

8605. The method of item 8499 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

8606. The method of item 8499 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

8607. The method of item 8499 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

8608. The method of item 8499 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

8609. The method of item 8499 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

8610. The method of item 8499 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

8611. The method of item 8499 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

8612. The method of item 8499 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

8613. The method of item 8499 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

8614. The method of item 8499 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

8615. The method of item 8499 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

8616. The method of item 8499 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8617. The method of item 8499 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8618. The method of item 8499 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8619. The method of item 8499 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

8620. The method of item 8499 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8621. The method of item 8499 wherein the implant is, or comprises, avalved sterilization device for surgical insertion into the VasDeferens.

8622. The method of item 8499 wherein the implant is, or comprises, areversible male sterilization device.

8623. The method of item 8499 wherein the implant is, or comprises, avasectomy clip.

8624. The method of item 8499 wherein the implant is, or comprises, avasectomy suture.

8625. The method of item 8499 wherein the implant is implanted in theVas Deferens.

8626. A method of making a medical device comprising combining i)gastric restriction implant and ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

8627. The method of item 8626 wherein the fibrosing agent promotesregeneration.

8628. The method of item 8626 wherein the fibrosing agent promotesangiogenesis.

8629. The method of item 8626 wherein the fibrosing agent promotesfibroblast migration.

8630. The method of item 8626 wherein the fibrosing agent promotesfibroblast proliferation.

8631. The method of item 8626 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

8632. The method of item 8626 wherein the fibrosing agent promotestissue remodeling.

8633. The method of item 8626 wherein the fibrosing agent is an arterialvessel wall irritant.

8634. The method of item 8626 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8635. The method of item 8626 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8636. The method of item 8626 wherein the fibrosing agent is orcomprises silk.

8637. The method of item 8626 wherein the fibrosing agent is orcomprises mineral particles.

8638. The method of item 8626 wherein the fibrosing agent is orcomprises chitosan.

8639. The method of item 8626 wherein the fibrosing agent is orcomprises polylysine.

8640. The method of item 8626 wherein the fibrosing agent is orcomprises fibronectin.

8641. The method of item 8626 wherein the fibrosing agent is orcomprises bleomycin.

8642. The method of item 8626 wherein the fibrosing agent is orcomprises CTGF.

8643. The method of item 8626 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

8644. The method of item 8626 wherein the fibrosing agent is in the formof a particulate.

8645. The method of item 8626 wherein the composition further comprisesan inflammatory cytokine.

8646. The method of item 8626 wherein the composition further comprisesan agent that stimulates cell proliferation.

8647. The method of item 8626 wherein the composition is in the form ofa gel or paste.

8648. The method of item 8626 wherein the fibrosing agent is in the formof tufts.

8649. The method of item 8626 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8650. The method of item 8626 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8651. The method of item 8626, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

8652. The method of item 8626, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

8653. The method of item 8626, wherein the implant is combined with acoating, and the coating directly contacts the device.

8654. The method of item 8626, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

8655. The method of item 8626, wherein the implant is combined with acoating, and the coating partially covers the device.

8656. The method of item 8626, wherein the implant is combined with acoating, and the coating completely covers the device.

8657. The method of item 8626, wherein the implant is combined with acoating, and the coating is a uniform coating.

8658. The method of item 8626, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

8659. The method of item 8626, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

8660. The method of item 8626 wherein the implant is combined with acoating, and the coating is a patterned coating.

8661. The method of item 8626, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

8662. The method of item 8626, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

8663. The method of item 8626, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

8664. The method of item 8626, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

8665. The method of item 8626, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

8666. The method of item 8626, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

8667. The method of item 8626, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

8668. The method of item 8626, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

8669. The method of item 8626, wherein the implant is combined with acoating, and the coating further comprises a polymer.

8670. The method of item 8626, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

8671. The method of item 8626, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

8672. The method of item 8626, wherein the device comprises a polymer.

8673. The method of item 8626, wherein the device comprises a polymer,and the polymer is a component of the composition.

8674. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a copolymer.

8675. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

8676. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

8677. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

8678. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

8679. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

8680. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

8681. The method of item 8626, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

8682. The method of item 8626, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

8683. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

8684. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is an elastomer.

8685. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

8686. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

8687. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

8688. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

8689. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

8690. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a macromer.

8691. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

8692. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

8693. The method of item 8626, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

8694. The method of item 8626 wherein the fibrosing agent is locatedwithin pores or holes of the device.

8695. The method of item 8626 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

8696. The method of item 8626, wherein the implant is further combinedwith a second pharmaceutically active agent.

8697. The method of item 8626, wherein the implant is further combinedwith an anti-inflammatory agent.

8698. The method of item 8626 wherein the implant is further combinedwith an agent that inhibits infection.

8699. The method of item 8626, wherein the implant is further combinedwith an anthracycline.

8700. The method of item 8626, wherein the implant is further combinedwith doxorubicin.

8701. The method of item 8626, wherein the implant is further combinedwith mitoxantrone.

8702. The method of item 8626, wherein the implant is further combinedwith a fluoropyrimidine.

8703. The method of item 8626, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

8704. The method of item 8626, wherein the implant is further combinedwith a folic acid antagonist.

8705. The method of item 8626, wherein the implant is further combinedwith methotrexate.

8706. The method of item 8626, wherein the implant is further combinedwith a podophylotoxin.

8707. The method of item 8626, wherein the implant is further combinedwith etoposide.

8708. The method of item 8626 wherein the implant is further combinedwith a camptothecin.

8709. The method of item 8626, wherein the implant is further combinedwith a hydroxyurea.

8710. The method of item 8626, wherein the implant is further combinedwith a platinum complex.

8711. The method of item 8626, wherein the implant is further combinedwith cisplatin.

8712. The method of item 8626, wherein the implant is further combinedwith an anti-thrombotic agent.

8713. The method of item 8626, wherein the implant is further combinedwith a visualization agent.

8714. The method of item 8626, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

8715. The method of item 8626, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

8716. The method of item 8626, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

8717. The method of item 8626, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

8718. The method of item 8626, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

8719. The method of item 8626, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

8720. The method of item 8626, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

8721. The method of item 8626, wherein the implant is further combinedwith an echogenic material.

8722. The method of item 8626, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

8723. The method of item 8626 wherein the device is sterilized.

8724. The method of item 8626 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

8725. The method of item 8626 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

8726. The method of item 8626 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

8727. The method of item 8626 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

8728. The method of item 8626 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

8729. The method of item 8626 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

8730. The method of item 8626 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

8731. The method of item 8626 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

8732. The method of item 8626 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

8733. The method of item 8626 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

8734. The method of item 8626 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

8735. The method of item 8626 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

8736. The method of item 8626 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

8737. The method of item 8626 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

8738. The method of item 8626 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

8739. The method of item 8626 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

8740. The method of item 8626 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

8741. The method of item 8626 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

8742. The method of item 8626 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

8743. The method of item 8626 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8744. The method of item 8626 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8745. The method of item 8626 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8746. The method of item 8626 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

8747. The method of item 8626 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8748. The method of item 8626 wherein the implant is, or comprises, aninflatable cuff.

8749. The method of item 8626 wherein the implant is, or comprises, aspace-occupying device.

8750. A method of making a medical device comprising combining i) asuture-based endoluminal implant for partitioning a stomach, with ii) afibrosing agent or a composition comprising a fibrosing agent, where thefibrosing agent induces a fibrotic response between the device and apatient in which the device is implanted.

8751. The method of item 8750 wherein the fibrosing agent promotesregeneration.

8752. The method of item 8750 wherein the fibrosing agent promotesangiogenesis.

8753. The method of item 8750 wherein the fibrosing agent promotesfibroblast migration.

8754. The method of item 8750 wherein the fibrosing agent promotesfibroblast proliferation.

8755. The method of item 8750 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

8756. The method of item 8750 wherein the fibrosing agent promotestissue remodeling.

8757. The method of item 8750 wherein the fibrosing agent is an arterialvessel wall irritant.

8758. The method of item 8750 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8759. The method of item 8750 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8760. The method of item 8750 wherein the fibrosing agent is orcomprises silk.

8761. The method of item 8750 wherein the fibrosing agent is orcomprises mineral particles.

8762. The method of item 8750 wherein the fibrosing agent is orcomprises chitosan.

8763. The method of item 8750 wherein the fibrosing agent is orcomprises polylysine.

8764. The method of item 8750 wherein the fibrosing agent is orcomprises fibronectin.

8765. The method of item 8750 wherein the fibrosing agent is orcomprises bleomycin.

8766. The method of item 8750 wherein the fibrosing agent is orcomprises CTGF.

8767. The method of item 8750 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

8768. The method of item 8750 wherein the fibrosing agent is in the formof a particulate.

8769. The method of item 8750 wherein the composition further comprisesan inflammatory cytokine.

8770. The method of item 8750 wherein the composition further comprisesan agent that stimulates cell proliferation.

8771. The method of item 8750 wherein the composition is in the form ofa gel or paste.

8772. The method of item 8750 wherein the fibrosing agent is in the formof tufts.

8773. The method of item 8750 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8774. The method of item 8750 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8775. The method of item 8750, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

8776. The method of item 8750, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

8777. The method of item 8750, wherein the implant is combined with acoating, and the coating directly contacts the device.

8778. The method of item 8750, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

8779. The method of item 8750, wherein the implant is combined with acoating, and the coating partially covers the device.

8780. The method of item 8750, wherein the implant is combined with acoating, and the coating completely covers the device.

8781. The method of item 8750, wherein the implant is combined with acoating, and the coating is a uniform coating.

8782. The method of item 8750, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

8783. The method of item 8750, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

8784. The method of item 8750 wherein the implant is combined with acoating, and the coating is a patterned coating.

8785. The method of item 8750, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

8786. The method of item 8750, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

8787. The method of item 8750, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

8788. The method of item 8750, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

8789. The method of item 8750, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

8790. The method of item 8750, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

8791. The method of item 8750, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

8792. The method of item 8750, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

8793. The method of item 8750, wherein the implant is combined with acoating, and the coating further comprises a polymer.

8794. The method of item 8750, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

8795. The method of item 8750, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

8796. The method of item 8750, wherein the device comprises a polymer.

8797. The method of item 8750, wherein the device comprises a polymer,and the polymer is a component of the composition.

8798. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a copolymer.

8799. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

8800. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

8801. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

8802. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

8803. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

8804. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

8805. The method of item 8750, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

8806. The method of item 8750, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

8807. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

8808. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is an elastomer.

8809. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

8810. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

8811. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

8812. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

8813. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

8814. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a macromer.

8815. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

8816. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

8817. The method of item 8750, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

8818. The method of item 8750 wherein the fibrosing agent is locatedwithin pores or holes of the device.

8819. The method of item 8750 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

8820. The method of item 8750, wherein the implant is further combinedwith a second pharmaceutically active agent.

8821. The method of item 8750, wherein the implant is further combinedwith an anti-inflammatory agent.

8822. The method of item 8750 wherein the implant is further combinedwith an agent that inhibits infection.

8823. The method of item 8750, wherein the implant is further combinedwith an anthracycline.

8824. The method of item 8750, wherein the implant is further combinedwith doxorubicin.

8825. The method of item 8750, wherein the implant is further combinedwith mitoxantrone.

8826. The method of item 8750, wherein the implant is further combinedwith a fluoropyrimidine.

8827. The method of item 8750, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

8828. The method of item 8750, wherein the implant is further combinedwith a folic acid antagonist.

8829. The method of item 8750, wherein the implant is further combinedwith methotrexate.

8830. The method of item 8750, wherein the implant is further combinedwith a podophylotoxin.

8831. The method of item 8750, wherein the implant is further combinedwith etoposide.

8832. The method of item 8750 wherein the implant is further combinedwith a camptothecin.

8833. The method of item 8750, wherein the implant is further combinedwith a hydroxyurea.

8834. The method of item 8750, wherein the implant is further combinedwith a platinum complex.

8835. The method of item 8750, wherein the implant is further combinedwith cisplatin.

8836. The method of item 8750, wherein the implant is further combinedwith an anti-thrombotic agent.

8837. The method of item 8750, wherein the implant is further combinedwith a visualization agent.

8838. The method of item 8750, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

8839. The method of item 8750, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

8840. The method of item 8750, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

8841. The method of item 8750, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

8842. The method of item 8750, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

8843. The method of item 8750, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

8844. The method of item 8750, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

8845. The method of item 8750, wherein the implant is further combinedwith an echogenic material.

8846. The method of item 8750, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

8847. The method of item 8750 wherein the device is sterilized.

8848. The method of item 8750 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

8849. The method of item 8750 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

8850. The method of item 8750 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

8851. The method of item 8750 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

8852. The method of item 8750 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

8853. The method of item 8750 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

8854. The method of item 8750 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

8855. The method of item 8750 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

8856. The method of item 8750 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

8857. The method of item 8750 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

8858. The method of item 8750 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

8859. The method of item 8750 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

8860. The method of item 8750 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

8861. The method of item 8750 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

8862. The method of item 8750 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

8863. The method of item 8750 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

8864. The method of item 8750 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

8865. The method of item 8750 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

8866. The method of item 8750 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

8867. The method of item 8750 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8868. The method of item 8750 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8869. The method of item 8750 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8870. The method of item 8750 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

8871. The method of item 8750 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8872. A method of making a medical device comprising combining i) anelectrostimulation implant for partitioning a stomach, with ii) afibrosing agent or a composition comprising a fibrosing agent, where thefibrosing agent induces a fibrotic response between the device and apatient in which the device is implanted.

8873. The method of item 8872 wherein the fibrosing agent promotesregeneration.

8874. The method of item 8872 wherein the fibrosing agent promotesangiogenesis.

8875. The method of item 8872 wherein the fibrosing agent promotesfibroblast migration.

8876. The method of item 8872 wherein the fibrosing agent promotesfibroblast proliferation.

8877. The method of item 8872 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

8878. The method of item 8872 wherein the fibrosing agent promotestissue remodeling.

8879. The method of item 8872 wherein the fibrosing agent is an arterialvessel wall irritant.

8880. The method of item 8872 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8881. The method of item 8872 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8882. The method of item 8872 wherein the fibrosing agent is orcomprises silk.

8883. The method of item 8872 wherein the fibrosing agent is orcomprises mineral particles.

8884. The method of item 8872 wherein the fibrosing agent is orcomprises chitosan.

8885. The method of item 8872 wherein the fibrosing agent is orcomprises polylysine.

8886. The method of item 8872 wherein the fibrosing agent is orcomprises fibronectin.

8887. The method of item 8872 wherein the fibrosing agent is orcomprises bleomycin.

8888. The method of item 8872 wherein the fibrosing agent is orcomprises CTGF.

8889. The method of item 8872 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

8890. The method of item 8872 wherein the fibrosing agent is in the formof a particulate.

8891. The method of item 8872 wherein the composition further comprisesan inflammatory cytokine.

8892. The method of item 8872 wherein the composition further comprisesan agent that stimulates cell proliferation.

8893. The method of item 8872 wherein the composition is in the form ofa gel or paste.

8894. The method of item 8872 wherein the fibrosing agent is in the formof tufts.

8895. The method of item 8872 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

8896. The method of item 8872 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

8897. The method of item 8872, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

8898. The method of item 8872, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

8899. The method of item 8872, wherein the implant is combined with acoating, and the coating directly contacts the device.

8900. The method of item 8872, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

8901. The method of item 8872, wherein the implant is combined with acoating, and the coating partially covers the device.

8902. The method of item 8872, wherein the implant is combined with acoating, and the coating completely covers the device.

8903. The method of item 8872, wherein the implant is combined with acoating, and the coating is a uniform coating.

8904. The method of item 8872, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

8905. The method of item 8872, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

8906. The method of item 8872 wherein the implant is combined with acoating, and the coating is a patterned coating.

8907. The method of item 8872, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

8908. The method of item 8872, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

8909. The method of item 8872, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

8910. The method of item 8872, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

8911. The method of item 8872, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

8912. The method of item 8872, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

8913. The method of item 8872, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

8914. The method of item 8872, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

8915. The method of item 8872, wherein the implant is combined with acoating, and the coating further comprises a polymer.

8916. The method of item 8872, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

8917. The method of item 8872, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

8918. The method of item 8872, wherein the device comprises a polymer.

8919. The method of item 8872, wherein the device comprises a polymer,and the polymer is a component of the composition.

8920. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a copolymer.

8921. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

8922. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

8923. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

8924. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

8925. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

8926. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

8927. The method of item 8872, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

8928. The method of item 8872, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

8929. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

8930. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is an elastomer.

8931. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

8932. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

8933. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

8934. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

8935. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

8936. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a macromer.

8937. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

8938. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

8939. The method of item 8872, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

8940. The method of item 8872 wherein the fibrosing agent is locatedwithin pores or holes of the device.

8941. The method of item 8872 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

8942. The method of item 8872, wherein the implant is further combinedwith a second pharmaceutically active agent.

8943. The method of item 8872, wherein the implant is further combinedwith an anti-inflammatory agent.

8944. The method of item 8872 wherein the implant is further combinedwith an agent that inhibits infection.

8945. The method of item 8872, wherein the implant is further combinedwith an anthracycline.

8946. The method of item 8872, wherein the implant is further combinedwith doxorubicin.

8947. The method of item 8872, wherein the implant is further combinedwith mitoxantrone.

8948. The method of item 8872, wherein the implant is further combinedwith a fluoropyrimidine.

8949. The method of item 8872, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

8950. The method of item 8872, wherein the implant is further combinedwith a folic acid antagonist.

8951. The method of item 8872, wherein the implant is further combinedwith methotrexate.

8952. The method of item 8872, wherein the implant is further combinedwith a podophylotoxin.

8953. The method of item 8872, wherein the implant is further combinedwith etoposide.

8954. The method of item 8872 wherein the implant is further combinedwith a camptothecin.

8955. The method of item 8872, wherein the implant is further combinedwith a hydroxyurea.

8956. The method of item 8872, wherein the implant is further combinedwith a platinum complex.

8957. The method of item 8872, wherein the implant is further combinedwith cisplatin.

8958. The method of item 8872, wherein the implant is further combinedwith an anti-thrombotic agent.

8959. The method of item 8872, wherein the implant is further combinedwith a visualization agent.

8960. The method of item 8872, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

8961. The method of item 8872, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

8962. The method of item 8872, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

8963. The method of item 8872, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

8964. The method of item 8872, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

8965. The method of item 8872, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

8966. The method of item 8872, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

8967. The method of item 8872, wherein the implant is further combinedwith an echogenic material.

8968. The method of item 8872, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

8969. The method of item 8872 wherein the device is sterilized.

8970. The method of item 8872 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

8971. The method of item 8872 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

8972. The method of item 8872 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

8973. The method of item 8872 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

8974. The method of item 8872 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

8975. The method of item 8872 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

8976. The method of item 8872 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

8977. The method of item 8872 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

8978. The method of item 8872 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

8979. The method of item 8872 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

8980. The method of item 8872 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

8981. The method of item 8872 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

8982. The method of item 8872 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

8983. The method of item 8872 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

8984. The method of item 8872 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

8985. The method of item 8872 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

8986. The method of item 8872 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

8987. The method of item 8872 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

8988. The method of item 8872 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

8989. The method of item 8872 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8990. The method of item 8872 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8991. The method of item 8872 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8992. The method of item 8872 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

8993. The method of item 8872 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

8994. The method of item 8872 wherein the implant is a neuralelectrostimulation implant.

8995. The method of item 8872 wherein the implant is a non-neuralelectrostimulation implant.

8996. A method of making a medical device comprising combining i) a softpalate implant, with ii) a fibrosing agent or a composition comprising afibrosing agent, where the fibrosing agent induces a fibrotic responsebetween the device and a patient in which the device is implanted.

8997. The method of item 8996 wherein the fibrosing agent promotesregeneration.

8998. The method of item 8996 wherein the fibrosing agent promotesangiogenesis.

8999. The method of item 8996 wherein the fibrosing agent promotesfibroblast migration.

9000. The method of item 8996 wherein the fibrosing agent promotesfibroblast proliferation.

9001. The method of item 8996 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

9002. The method of item 8996 wherein the fibrosing agent promotestissue remodeling.

9003. The method of item 8996 wherein the fibrosing agent is an arterialvessel wall irritant.

9004. The method of item 8996 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9005. The method of item 8996 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9006. The method of item 8996 wherein the fibrosing agent is orcomprises silk.

9007. The method of item 8996 wherein the fibrosing agent is orcomprises mineral particles.

9008. The method of item 8996 wherein the fibrosing agent is orcomprises chitosan.

9009. The method of item 8996 wherein the fibrosing agent is orcomprises polylysine.

9010. The method of item 8996 wherein the fibrosing agent is orcomprises fibronectin.

9011. The method of item 8996 wherein the fibrosing agent is orcomprises bleomycin.

9012. The method of item 8996 wherein the fibrosing agent is orcomprises CTGF.

9013. The method of item 8996 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

9014. The method of item 8996 wherein the fibrosing agent is in the formof a particulate.

9015. The method of item 8996 wherein the composition further comprisesan inflammatory cytokine.

9016. The method of item 8996 wherein the composition further comprisesan agent that stimulates cell proliferation.

9017. The method of item 8996 wherein the composition is in the form ofa gel or paste.

9018. The method of item 8996 wherein the fibrosing agent is in the formof tufts.

9019. The method of item 8996 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9020. The method of item 8996 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9021. The method of item 8996, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

9022. The method of item 8996, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

9023. The method of item 8996, wherein the implant is combined with acoating, and the coating directly contacts the device.

9024. The method of item 8996, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

9025. The method of item 8996, wherein the implant is combined with acoating, and the coating partially covers the device.

9026. The method of item 8996, wherein the implant is combined with acoating, and the coating completely covers the device.

9027. The method of item 8996, wherein the implant is combined with acoating, and the coating is a uniform coating.

9028. The method of item 8996, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

9029. The method of item 8996, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

9030. The method of item 8996 wherein the implant is combined with acoating, and the coating is a patterned coating.

9031. The method of item 8996, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

9032. The method of item 8996, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

9033. The method of item 8996, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

9034. The method of item 8996, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

9035. The method of item 8996, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

9036. The method of item 8996, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

9037. The method of item 8996, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

9038. The method of item 8996, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

9039. The method of item 8996, wherein the implant is combined with acoating, and the coating further comprises a polymer.

9040. The method of item 8996, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

9041. The method of item 8996, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

9042. The method of item 8996, wherein the device comprises a polymer.

9043. The method of item 8996, wherein the device comprises a polymer,and the polymer is a component of the composition.

9044. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a copolymer.

9045. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

9046. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

9047. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

9048. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

9049. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

9050. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

9051. The method of item 8996, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

9052. The method of item 8996, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

9053. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

9054. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is an elastomer.

9055. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

9056. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

9057. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

9058. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

9059. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

9060. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a macromer.

9061. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

9062. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

9063. The method of item 8996, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

9064. The method of item 8996 wherein the fibrosing agent is locatedwithin pores or holes of the device.

9065. The method of item 8996 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

9066. The method of item 8996, wherein the implant is further combinedwith a second pharmaceutically active agent.

9067. The method of item 8996, wherein the implant is further combinedwith an anti-inflammatory agent.

9068. The method of item 8996 wherein the implant is further combinedwith an agent that inhibits infection.

9069. The method of item 8996, wherein the implant is further combinedwith an anthracycline.

9070. The method of item 8996, wherein the implant is further combinedwith doxorubicin.

9071. The method of item 8996, wherein the implant is further combinedwith mitoxantrone.

9072. The method of item 8996, wherein the implant is further combinedwith a fluoropyrimidine.

9073. The method of item 8996, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

9074. The method of item 8996, wherein the implant is further combinedwith a folic acid antagonist.

9075. The method of item 8996, wherein the implant is further combinedwith methotrexate.

9076. The method of item 8996, wherein the implant is further combinedwith a podophylotoxin.

9077. The method of item 8996, wherein the implant is further combinedwith etoposide.

9078. The method of item 8996 wherein the implant is further combinedwith a camptothecin.

9079. The method of item 8996, wherein the implant is further combinedwith a hydroxyurea.

9080. The method of item 8996, wherein the implant is further combinedwith a platinum complex.

9081. The method of item 8996, wherein the implant is further combinedwith cisplatin.

9082. The method of item 8996, wherein the implant is further combinedwith an anti-thrombotic agent.

9083. The method of item 8996, wherein the implant is further combinedwith a visualization agent.

9084. The method of item 8996, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

9085. The method of item 8996, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

9086. The method of item 8996, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

9087. The method of item 8996, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

9088. The method of item 8996, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

9089. The method of item 8996, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

9090. The method of item 8996, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

9091. The method of item 8996, wherein the implant is further combinedwith an echogenic material.

9092. The method of item 8996, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

9093. The method of item 8996 wherein the device is sterilized.

9094. The method of item 8996 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

9095. The method of item 8996 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

9096. The method of item 8996 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

9097. The method of item 8996 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

9098. The method of item 8996 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

9099. The method of item 8996 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

9100. The method of item 8996 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

9101. The method of item 8996 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

9102. The method of item 8996 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

9103. The method of item 8996 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

9104. The method of item 8996 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

9105. The method of item 8996 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

9106. The method of item 8996 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

9107. The method of item 8996 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

9108. The method of item 8996 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

9109. The method of item 8996 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

9110. The method of item 8996 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

9111. The method of item 8996 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

9112. The method of item 8996 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

9113. The method of item 8996 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9114. The method of item 8996 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9115. The method of item 8996 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9116. The method of item 8996 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

9117. The method of item 8996 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9118. A method of making a medical device comprising combining i) avascular coil implant, with ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

9119. The method of item 9118 wherein the fibrosing agent promotesregeneration.

9120. The method of item 9118 wherein the fibrosing agent promotesangiogenesis.

9121. The method of item 9118 wherein the fibrosing agent promotesfibroblast migration.

9122. The method of item 9118 wherein the fibrosing agent promotesfibroblast proliferation.

9123. The method of item 9118 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

9124. The method of item 9118 wherein the fibrosing agent promotestissue remodeling.

9125. The method of item 9118 wherein the fibrosing agent is an arterialvessel wall irritant.

9126. The method of item 9118 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9127. The method of item 9118 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9128. The method of item 9118 wherein the fibrosing agent is orcomprises silk.

9129. The method of item 9118 wherein the fibrosing agent is orcomprises mineral particles.

9130. The method of item 9118 wherein the fibrosing agent is orcomprises chitosan.

9131. The method of item 9118 wherein the fibrosing agent is orcomprises polylysine.

9132. The method of item 9118 wherein the fibrosing agent is orcomprises fibronectin.

9133. The method of item 9118 wherein the fibrosing agent is orcomprises bleomycin.

9134. The method of item 9118 wherein the fibrosing agent is orcomprises CTGF.

9135. The method of item 9118 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

9136. The method of item 9118 wherein the fibrosing agent is in the formof a particulate.

9137. The method of item 9118 wherein the composition further comprisesan inflammatory cytokine.

9138. The method of item 9118 wherein the composition further comprisesan agent that stimulates cell proliferation.

9139. The method of item 9118 wherein the composition is in the form ofa gel or paste.

9140. The method of item 9118 wherein the fibrosing agent is in the formof tufts.

9141. The method of item 9118 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9142. The method of item 9118 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9143. The method of item 9118, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

9144. The method of item 9118, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

9145. The method of item 9118, wherein the implant is combined with acoating, and the coating directly contacts the device.

9146. The method of item 9118, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

9147. The method of item 9118, wherein the implant is combined with acoating, and the coating partially covers the device.

9148. The method of item 9118, wherein the implant is combined with acoating, and the coating completely covers the device.

9149. The method of item 9118, wherein the implant is combined with acoating, and the coating is a uniform coating.

9150. The method of item 9118, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

9151. The method of item 9118, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

9152. The method of item 9118 wherein the implant is combined with acoating, and the coating is a patterned coating.

9153. The method of item 9118, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

9154. The method of item 9118, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

9155. The method of item 9118, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

9156. The method of item 9118, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

9157. The method of item 9118, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

9158. The method of item 9118, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

9159. The method of item 9118, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

9160. The method of item 9118, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

9161. The method of item 9118, wherein the implant is combined with acoating, and the coating further comprises a polymer.

9162. The method of item 9118, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

9163. The method of item 9118, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

9164. The method of item 9118, wherein the device comprises a polymer.

9165. The method of item 9118, wherein the device comprises a polymer,and the polymer is a component of the composition.

9166. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a copolymer.

9167. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

9168. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

9169. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

9170. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

9171. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

9172. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

9173. The method of item 9118, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

9174. The method of item 9118, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

9175. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

9176. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is an elastomer.

9177. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

9178. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

9179. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

9180. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

9181. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

9182. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a macromer.

9183. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

9184. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

9185. The method of item 9118, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

9186. The method of item 9118 wherein the fibrosing agent is locatedwithin pores or holes of the device.

9187. The method of item 9118 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

9188. The method of item 9118, wherein the implant is further combinedwith a second pharmaceutically active agent.

9189. The method of item 9118, wherein the implant is further combinedwith an anti-inflammatory agent.

9190. The method of item 9118 wherein the implant is further combinedwith an agent that inhibits infection.

9191. The method of item 9118, wherein the implant is further combinedwith an anthracycline.

9192. The method of item 9118, wherein the implant is further combinedwith doxorubicin.

9193. The method of item 9118, wherein the implant is further combinedwith mitoxantrone.

9194. The method of item 9118, wherein the implant is further combinedwith a fluoropyrimidine.

9195. The method of item 9118, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

9196. The method of item 9118, wherein the implant is further combinedwith a folic acid antagonist.

9197. The method of item 9118, wherein the implant is further combinedwith methotrexate.

9198. The method of item 9118, wherein the implant is further combinedwith a podophylotoxin.

9199. The method of item 9118, wherein the implant is further combinedwith etoposide.

9200. The method of item 9118 wherein the implant is further combinedwith a camptothecin.

9201. The method of item 9118, wherein the implant is further combinedwith a hydroxyurea.

9202. The method of item 9118, wherein the implant is further combinedwith a platinum complex.

9203. The method of item 9118, wherein the implant is further combinedwith cisplatin.

9204. The method of item 9118, wherein the implant is further combinedwith an anti-thrombotic agent.

9205. The method of item 9118, wherein the implant is further combinedwith a visualization agent.

9206. The method of item 9118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

9207. The method of item 9118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

9208. The method of item 9118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

9209. The method of item 9118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

9210. The method of item 9118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

9211. The method of item 9118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

9212. The method of item 9118, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

9213. The method of item 9118, wherein the implant is further combinedwith an echogenic material.

9214. The method of item 9118, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

9215. The method of item 9118 wherein the device is sterilized.

9216. The method of item 9118 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

9217. The method of item 9118 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

9218. The method of item 9118 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

9219. The method of item 9118 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

9220. The method of item 9118 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

9221. The method of item 9118 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

9222. The method of item 9118 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

9223. The method of item 9118 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

9224. The method of item 9118 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

9225. The method of item 9118 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

9226. The method of item 9118 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

9227. The method of item 9118 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

9228. The method of item 9118 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

9229. The method of item 9118 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

9230. The method of item 9118 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

9231. The method of item 9118 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

9232. The method of item 9118 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

9233. The method of item 9118 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

9234. The method of item 9118 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

9235. The method of item 9118 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9236. The method of item 9118 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9237. The method of item 9118 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9238. The method of item 9118 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

9239. The method of item 9118 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9240. The method of item 9118 wherein the vascular coil implantcomprises fluorinated polymer.

9241. The method of item 9118 wherein the vascular coil implant isporous.

9242. The method of item 9118 wherein the vascular coil implantcomprises a bioactive material.

9243. The method of item 9118 wherein the vascular coil implant isbiologically inert.

9244. The method of item 9118 wherein the vascular coil implant has afirst state prior to insertion and a second state post insertion.

9245. A method of making a medical device comprising combining i) avaso-occlusive coil implant, with ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

9246. The method of item 9245 wherein the fibrosing agent promotesregeneration.

9247. The method of item 9245 wherein the fibrosing agent promotesangiogenesis.

9248. The method of item 9245 wherein the fibrosing agent promotesfibroblast migration.

9249. The method of item 9245 wherein the fibrosing agent promotesfibroblast proliferation.

9250. The method of item 9245 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

9251. The method of item 9245 wherein the fibrosing agent promotestissue remodeling.

9252. The method of item 9245 wherein the fibrosing agent is an arterialvessel wall irritant.

9253. The method of item 9245 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9254. The method of item 9245 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9255. The method of item 9245 wherein the fibrosing agent is orcomprises silk.

9256. The method of item 9245 wherein the fibrosing agent is orcomprises mineral particles.

9257. The method of item 9245 wherein the fibrosing agent is orcomprises chitosan.

9258. The method of item 9245 wherein the fibrosing agent is orcomprises polylysine.

9259. The method of item 9245 wherein the fibrosing agent is orcomprises fibronectin.

9260. The method of item 9245 wherein the fibrosing agent is orcomprises bleomycin.

9261. The method of item 9245 wherein the fibrosing agent is orcomprises CTGF.

9262. The method of item 9245 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

9263. The method of item 9245 wherein the fibrosing agent is in the formof a particulate.

9264. The method of item 9245 wherein the composition further comprisesan inflammatory cytokine.

9265. The method of item 9245 wherein the composition further comprisesan agent that stimulates cell proliferation.

9266. The method of item 9245 wherein the composition is in the form ofa gel or paste.

9267. The method of item 9245 wherein the fibrosing agent is in the formof tufts.

9268. The method of item 9245 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9269. The method of item 9245 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9270. The method of item 9245, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

9271. The method of item 9245, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

9272. The method of item 9245, wherein the implant is combined with acoating, and the coating directly contacts the device.

9273. The method of item 9245, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

9274. The method of item 9245, wherein the implant is combined with acoating, and the coating partially covers the device.

9275. The method of item 9245, wherein the implant is combined with acoating, and the coating completely covers the device.

9276. The method of item 9245, wherein the implant is combined with acoating, and the coating is a uniform coating.

9277. The method of item 9245, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

9278. The method of item 9245, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

9279. The method of item 9245 wherein the implant is combined with acoating, and the coating is a patterned coating.

9280. The method of item 9245, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

9281. The method of item 9245, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

9282. The method of item 9245, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

9283. The method of item 9245, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

9284. The method of item 9245, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

9285. The method of item 9245, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

9286. The method of item 9245, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

9287. The method of item 9245, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

9288. The method of item 9245, wherein the implant is combined with acoating, and the coating further comprises a polymer.

9289. The method of item 9245, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

9290. The method of item 9245, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

9291. The method of item 9245, wherein the device comprises a polymer.

9292. The method of item 9245, wherein the device comprises a polymer,and the polymer is a component of the composition.

9293. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a copolymer.

9294. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

9295. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

9296. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

9297. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

9298. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

9299. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

9300. The method of item 9245, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

9301. The method of item 9245, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

9302. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

9303. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is an elastomer.

9304. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

9305. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

9306. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

9307. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

9308. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

9309. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a macromer.

9310. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

9311. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

9312. The method of item 9245, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

9313. The method of item 9245 wherein the fibrosing agent is locatedwithin pores or holes of the device.

9314. The method of item 9245 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

9315. The method of item 9245, wherein the implant is further combinedwith a second pharmaceutically active agent.

9316. The method of item 9245, wherein the implant is further combinedwith an anti-inflammatory agent.

9317. The method of item 9245 wherein the implant is further combinedwith an agent that inhibits infection.

9318. The method of item 9245, wherein the implant is further combinedwith an anthracycline.

9319. The method of item 9245, wherein the implant is further combinedwith doxorubicin.

9320. The method of item 9245, wherein the implant is further combinedwith mitoxantrone.

9321. The method of item 9245, wherein the implant is further combinedwith a fluoropyrimidine.

9322. The method of item 9245, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

9323. The method of item 9245, wherein the implant is further combinedwith a folic acid antagonist.

9324. The method of item 9245, wherein the implant is further combinedwith methotrexate.

9325. The method of item 9245, wherein the implant is further combinedwith a podophylotoxin.

9326. The method of item 9245, wherein the implant is further combinedwith etoposide.

9327. The method of item 9245 wherein the implant is further combinedwith a camptothecin.

9328. The method of item 9245, wherein the implant is further combinedwith a hydroxyurea.

9329. The method of item 9245, wherein the implant is further combinedwith a platinum complex.

9330. The method of item 9245, wherein the implant is further combinedwith cisplatin.

9331. The method of item 9245, wherein the implant is further combinedwith an anti-thrombotic agent.

9332. The method of item 9245, wherein the implant is further combinedwith a visualization agent.

9333. The method of item 9245, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

9334. The method of item 9245, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

9335. The method of item 9245, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

9336. The method of item 9245, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

9337. The method of item 9245, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

9338. The method of item 9245, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

9339. The method of item 9245, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

9340. The method of item 9245, wherein the implant is further combinedwith an echogenic material.

9341. The method of item 9245, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

9342. The method of item 9245 wherein the device is sterilized.

9343. The method of item 9245 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

9344. The method of item 9245 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

9345. The method of item 9245 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

9346. The method of item 9245 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

9347. The method of item 9245 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

9348. The method of item 9245 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

9349. The method of item 9245 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

9350. The method of item 9245 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

9351. The method of item 9245 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

9352. The method of item 9245 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

9353. The method of item 9245 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

9354. The method of item 9245 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

9355. The method of item 9245 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

9356. The method of item 9245 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

9357. The method of item 9245 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

9358. The method of item 9245 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

9359. The method of item 9245 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

9360. The method of item 9245 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

9361. The method of item 9245 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

9362. The method of item 9245 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9363. The method of item 9245 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9364. The method of item 9245 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9365. The method of item 9245 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

9366. The method of item 9245 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9367. A method of making a medical device comprising combining i) avaso-occlusion implant, with ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

9368. The method of item 9367 wherein the fibrosing agent promotesregeneration.

9369. The method of item 9367 wherein the fibrosing agent promotesangiogenesis.

9370. The method of item 9367 wherein the fibrosing agent promotesfibroblast migration.

9371. The method of item 9367 wherein the fibrosing agent promotesfibroblast proliferation.

9372. The method of item 9367 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

9373. The method of item 9367 wherein the fibrosing agent promotestissue remodeling.

9374. The method of item 9367 wherein the fibrosing agent is an arterialvessel wall irritant.

9375. The method of item 9367 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9376. The method of item 9367 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9377. The method of item 9367 wherein the fibrosing agent is orcomprises silk.

9378. The method of item 9367 wherein the fibrosing agent is orcomprises mineral particles.

9379. The method of item 9367 wherein the fibrosing agent is orcomprises chitosan.

9380. The method of item 9367 wherein the fibrosing agent is orcomprises polylysine.

9381. The method of item 9367 wherein the fibrosing agent is orcomprises fibronectin.

9382. The method of item 9367 wherein the fibrosing agent is orcomprises bleomycin.

9383. The method of item 9367 wherein the fibrosing agent is orcomprises CTGF.

9384. The method of item 9367 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

9385. The method of item 9367 wherein the fibrosing agent is in the formof a particulate.

9386. The method of item 9367 wherein the composition further comprisesan inflammatory cytokine.

9387. The method of item 9367 wherein the composition further comprisesan agent that stimulates cell proliferation.

9388. The method of item 9367 wherein the composition is in the form ofa gel or paste.

9389. The method of item 9367 wherein the fibrosing agent is in the formof tufts.

9390. The method of item 9367 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9391. The method of item 9367 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9392. The method of item 9367, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

9393. The method of item 9367, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

9394. The method of item 9367, wherein the implant is combined with acoating, and the coating directly contacts the device.

9395. The method of item 9367, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

9396. The method of item 9367, wherein the implant is combined with acoating, and the coating partially covers the device.

9397. The method of item 9367, wherein the implant is combined with acoating, and the coating completely covers the device.

9398. The method of item 9367, wherein the implant is combined with acoating, and the coating is a uniform coating.

9399. The method of item 9367, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

9400. The method of item 9367, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

9401. The method of item 9367 wherein the implant is combined with acoating, and the coating is a patterned coating.

9402. The method of item 9367, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

9403. The method of item 9367, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

9404. The method of item 9367, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

9405. The method of item 9367, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

9406. The method of item 9367, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

9407. The method of item 9367, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

9408. The method of item 9367, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

9409. The method of item 9367, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

9410. The method of item 9367, wherein the implant is combined with acoating, and the coating further comprises a polymer.

9411. The method of item 9367, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

9412. The method of item 9367, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

9413. The method of item 9367, wherein the device comprises a polymer.

9414. The method of item 9367, wherein the device comprises a polymer,and the polymer is a component of the composition.

9415. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a copolymer.

9416. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

9417. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

9418. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

9419. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

9420. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

9421. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

9422. The method of item 9367, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

9423. The method of item 9367, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

9424. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

9425. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is an elastomer.

9426. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

9427. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

9428. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

9429. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

9430. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

9431. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a macromer.

9432. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

9433. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

9434. The method of item 9367, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

9435. The method of item 9367 wherein the fibrosing agent is locatedwithin pores or holes of the device.

9436. The method of item 9367 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

9437. The method of item 9367, wherein the implant is further combinedwith a second pharmaceutically active agent.

9438. The method of item 9367, wherein the implant is further combinedwith an anti-inflammatory agent.

9439. The method of item 9367 wherein the implant is further combinedwith an agent that inhibits infection.

9440. The method of item 9367, wherein the implant is further combinedwith an anthracycline.

9441. The method of item 9367, wherein the implant is further combinedwith doxorubicin.

9442. The method of item 9367, wherein the implant is further combinedwith mitoxantrone.

9443. The method of item 9367, wherein the implant is further combinedwith a fluoropyrimidine.

9444. The method of item 9367, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

9445. The method of item 9367, wherein the implant is further combinedwith a folic acid antagonist.

9446. The method of item 9367, wherein the implant is further combinedwith methotrexate.

9447. The method of item 9367, wherein the implant is further combinedwith a podophylotoxin.

9448. The method of item 9367, wherein the implant is further combinedwith etoposide.

9449. The method of item 9367 wherein the implant is further combinedwith a camptothecin.

9450. The method of item 9367, wherein the implant is further combinedwith a hydroxyurea.

9451. The method of item 9367, wherein the implant is further combinedwith a platinum complex.

9452. The method of item 9367, wherein the implant is further combinedwith cisplatin.

9453. The method of item 9367, wherein the implant is further combinedwith an anti-thrombotic agent.

9454. The method of item 9367, wherein the implant is further combinedwith a visualization agent.

9455. The method of item 9367, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

9456. The method of item 9367, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

9457. The method of item 9367, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

9458. The method of item 9367, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

9459. The method of item 9367, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

9460. The method of item 9367, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

9461. The method of item 9367, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

9462. The method of item 9367, wherein the implant is further combinedwith an echogenic material.

9463. The method of item 9367, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

9464. The method of item 9367 wherein the device is sterilized.

9465. The method of item 9367 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

9466. The method of item 9367 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

9467. The method of item 9367 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

9468. The method of item 9367 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

9469. The method of item 9367 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

9470. The method of item 9367 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

9471. The method of item 9367 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

9472. The method of item 9367 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

9473. The method of item 9367 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

9474. The method of item 9367 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

9475. The method of item 9367 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

9476. The method of item 9367 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

9477. The method of item 9367 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

9478. The method of item 9367 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

9479. The method of item 9367 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

9480. The method of item 9367 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

9481. The method of item 9367 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

9482. The method of item 9367 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

9483. The method of item 9367 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

9484. The method of item 9367 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9485. The method of item 9367 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9486. The method of item 9367 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9487. The method of item 9367 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

9488. The method of item 9367 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9489. A method of making a medical device comprising combining i) anon-coiled vaso-occlusive implant, with ii) a fibrosing agent or acomposition comprising a fibrosing agent, where the fibrosing agentinduces a fibrotic response between the device and a patient in whichthe device is implanted.

9490. The method of item 9489 wherein the fibrosing agent promotesregeneration.

9491. The method of item 9489 wherein the fibrosing agent promotesangiogenesis.

9492. The method of item 9489 wherein the fibrosing agent promotesfibroblast migration.

9493. The method of item 9489 wherein the fibrosing agent promotesfibroblast proliferation.

9494. The method of item 9489 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

9495. The method of item 9489 wherein the fibrosing agent promotestissue remodeling.

9496. The method of item 9489 wherein the fibrosing agent is an arterialvessel wall irritant.

9497. The method of item 9489 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9498. The method of item 9489 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9499. The method of item 9489 wherein the fibrosing agent is orcomprises silk.

9500. The method of item 9489 wherein the fibrosing agent is orcomprises mineral particles.

9501. The method of item 9489 wherein the fibrosing agent is orcomprises chitosan.

9502. The method of item 9489 wherein the fibrosing agent is orcomprises polylysine.

9503. The method of item 9489 wherein the fibrosing agent is orcomprises fibronectin.

9504. The method of item 9489 wherein the fibrosing agent is orcomprises bleomycin.

9505. The method of item 9489 wherein the fibrosing agent is orcomprises CTGF.

9506. The method of item 9489 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

9507. The method of item 9489 wherein the fibrosing agent is in the formof a particulate.

9508. The method of item 9489 wherein the composition further comprisesan inflammatory cytokine.

9509. The method of item 9489 wherein the composition further comprisesan agent that stimulates cell proliferation.

9510. The method of item 9489 wherein the composition is in the form ofa gel or paste.

9511. The method of item 9489 wherein the fibrosing agent is in the formof tufts.

9512. The method of item 9489 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9513. The method of item 9489 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9514. The method of item 9489, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

9515. The method of item 9489, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

9516. The method of item 9489, wherein the implant is combined with acoating, and the coating directly contacts the device.

9517. The method of item 9489, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

9518. The method of item 9489, wherein the implant is combined with acoating, and the coating partially covers the device.

9519. The method of item 9489, wherein the implant is combined with acoating, and the coating completely covers the device.

9520. The method of item 9489, wherein the implant is combined with acoating, and the coating is a uniform coating.

9521. The method of item 9489, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

9522. The method of item 9489, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

9523. The method of item 9489 wherein the implant is combined with acoating, and the coating is a patterned coating.

9524. The method of item 9489, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

9525. The method of item 9489, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

9526. The method of item 9489, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

9527. The method of item 9489, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

9528. The method of item 9489, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

9529. The method of item 9489, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

9530. The method of item 9489, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

9531. The method of item 9489, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

9532. The method of item 9489, wherein the implant is combined with acoating, and the coating further comprises a polymer.

9533. The method of item 9489, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

9534. The method of item 9489, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

9535. The method of item 9489, wherein the device comprises a polymer.

9536. The method of item 9489, wherein the device comprises a polymer,and the polymer is a component of the composition.

9537. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a copolymer.

9538. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

9539. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

9540. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

9541. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

9542. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

9543. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

9544. The method of item 9489, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

9545. The method of item 9489, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

9546. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

9547. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is an elastomer.

9548. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

9549. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

9550. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

9551. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

9552. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

9553. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a macromer.

9554. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

9555. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

9556. The method of item 9489, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

9557. The method of item 9489 wherein the fibrosing agent is locatedwithin pores or holes of the device.

9558. The method of item 9489 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

9559. The method of item 9489, wherein the implant is further combinedwith a second pharmaceutically active agent.

9560. The method of item 9489, wherein the implant is further combinedwith an anti-inflammatory agent.

9561. The method of item 9489 wherein the implant is further combinedwith an agent that inhibits infection.

9562. The method of item 9489, wherein the implant is further combinedwith an anthracycline.

9563. The method of item 9489, wherein the implant is further combinedwith doxorubicin.

9564. The method of item 9489, wherein the implant is further combinedwith mitoxantrone.

9565. The method of item 9489, wherein the implant is further combinedwith a fluoropyrimidine.

9566. The method of item 9489, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

9567. The method of item 9489, wherein the implant is further combinedwith a folic acid antagonist.

9568. The method of item 9489, wherein the implant is further combinedwith methotrexate.

9569. The method of item 9489, wherein the implant is further combinedwith a podophylotoxin.

9570. The method of item 9489, wherein the implant is further combinedwith etoposide.

9571. The method of item 9489 wherein the implant is further combinedwith a camptothecin.

9572. The method of item 9489, wherein the implant is further combinedwith a hydroxyurea.

9573. The method of item 9489, wherein the implant is further combinedwith a platinum complex.

9574. The method of item 9489, wherein the implant is further combinedwith cisplatin.

9575. The method of item 9489, wherein the implant is further combinedwith an anti-thrombotic agent.

9576. The method of item 9489, wherein the implant is further combinedwith a visualization agent.

9577. The method of item 9489, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

9578. The method of item 9489, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

9579. The method of item 9489, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

9580. The method of item 9489, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

9581. The method of item 9489, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

9582. The method of item 9489, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

9583. The method of item 9489, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

9584. The method of item 9489, wherein the implant is further combinedwith an echogenic material.

9585. The method of item 9489, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

9586. The method of item 9489 wherein the device is sterilized.

9587. The method of item 9489 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

9588. The method of item 9489 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

9589. The method of item 9489 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

9590. The method of item 9489 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

9591. The method of item 9489 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

9592. The method of item 9489 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

9593. The method of item 9489 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

9594. The method of item 9489 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

9595. The method of item 9489 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

9596. The method of item 9489 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

9597. The method of item 9489 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

9598. The method of item 9489 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

9599. The method of item 9489 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

9600. The method of item 9489 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

9601. The method of item 9489 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

9602. The method of item 9489 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

9603. The method of item 9489 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

9604. The method of item 9489 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

9605. The method of item 9489 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

9606. The method of item 9489 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9607. The method of item 9489 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9608. The method of item 9489 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9609. The method of item 9489 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

9610. The method of item 9489 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9611. The method of item 9489 wherein the implant is expandable.

9612. A method of making a medical device comprising combining i) ahernia mesh implant, with ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

9613. The method of item 9612 wherein the fibrosing agent promotesregeneration.

9614. The method of item 9612 wherein the fibrosing agent promotesangiogenesis.

9615. The method of item 9612 wherein the fibrosing agent promotesfibroblast migration.

9616. The method of item 9612 wherein the fibrosing agent promotesfibroblast proliferation.

9617. The method of item 9612 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

9618. The method of item 9612 wherein the fibrosing agent promotestissue remodeling.

9619. The method of item 9612 wherein the fibrosing agent is an arterialvessel wall irritant.

9620. The method of item 9612 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9621. The method of item 9612 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9622. The method of item 9612 wherein the fibrosing agent is orcomprises silk.

9623. The method of item 9612 wherein the fibrosing agent is orcomprises mineral particles.

9624. The method of item 9612 wherein the fibrosing agent is orcomprises chitosan.

9625. The method of item 9612 wherein the fibrosing agent is orcomprises polylysine.

9626. The method of item 9612 wherein the fibrosing agent is orcomprises fibronectin.

9627. The method of item 9612 wherein the fibrosing agent is orcomprises bleomycin.

9628. The method of item 9612 wherein the fibrosing agent is orcomprises CTGF.

9629. The method of item 9612 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

9630. The method of item 9612 wherein the fibrosing agent is in the formof a particulate.

9631. The method of item 9612 wherein the composition further comprisesan inflammatory cytokine.

9632. The method of item 9612 wherein the composition further comprisesan agent that stimulates cell proliferation.

9633. The method of item 9612 wherein the composition is in the form ofa gel or paste.

9634. The method of item 9612 wherein the fibrosing agent is in the formof tufts.

9635. The method of item 9612 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9636. The method of item 9612 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9637. The method of item 9612, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

9638. The method of item 9612, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

9639. The method of item 9612, wherein the implant is combined with acoating, and the coating directly contacts the device.

9640. The method of item 9612, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

9641. The method of item 9612, wherein the implant is combined with acoating, and the coating partially covers the device.

9642. The method of item 9612, wherein the implant is combined with acoating, and the coating completely covers the device.

9643. The method of item 9612, wherein the implant is combined with acoating, and the coating is a uniform coating.

9644. The method of item 9612, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

9645. The method of item 9612, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

9646. The method of item 9612 wherein the implant is combined with acoating, and the coating is a patterned coating.

9647. The method of item 9612, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

9648. The method of item 9612, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

9649. The method of item 9612, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

9650. The method of item 9612, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

9651. The method of item 9612, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

9652. The method of item 9612, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

9653. The method of item 9612, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

9654. The method of item 9612, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

9655. The method of item 9612, wherein the implant is combined with acoating, and the coating further comprises a polymer.

9656. The method of item 9612, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

9657. The method of item 9612, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

9658. The method of item 9612, wherein the device comprises a polymer.

9659. The method of item 9612, wherein the device comprises a polymer,and the polymer is a component of the composition.

9660. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a copolymer.

9661. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

9662. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

9663. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

9664. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

9665. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

9666. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

9667. The method of item 9612, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

9668. The method of item 9612, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

9669. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

9670. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is an elastomer.

9671. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

9672. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

9673. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

9674. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

9675. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

9676. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a macromer.

9677. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

9678. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

9679. The method of item 9612, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

9680. The method of item 9612 wherein the fibrosing agent is locatedwithin pores or holes of the device.

9681. The method of item 9612 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

9682. The method of item 9612, wherein the implant is further combinedwith a second pharmaceutically active agent.

9683. The method of item 9612, wherein the implant is further combinedwith an anti-inflammatory agent.

9684. The method of item 9612 wherein the implant is further combinedwith an agent that inhibits infection.

9685. The method of item 9612, wherein the implant is further combinedwith an anthracycline.

9686. The method of item 9612, wherein the implant is further combinedwith doxorubicin.

9687. The method of item 9612, wherein the implant is further combinedwith mitoxantrone.

9688. The method of item 9612, wherein the implant is further combinedwith a fluoropyrimidine.

9689. The method of item 9612, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

9690. The method of item 9612, wherein the implant is further combinedwith a folic acid antagonist.

9691. The method of item 9612, wherein the implant is further combinedwith methotrexate.

9692. The method of item 9612, wherein the implant is further combinedwith a podophylotoxin.

9693. The method of item 9612, wherein the implant is further combinedwith etoposide.

9694. The method of item 9612 wherein the implant is further combinedwith a camptothecin.

9695. The method of item 9612, wherein the implant is further combinedwith a hydroxyurea.

9696. The method of item 9612, wherein the implant is further combinedwith a platinum complex.

9697. The method of item 9612, wherein the implant is further combinedwith cisplatin.

9698. The method of item 9612, wherein the implant is further combinedwith an anti-thrombotic agent.

9699. The method of item 9612, wherein the implant is further combinedwith a visualization agent.

9700. The method of item 9612, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

9701. The method of item 9612, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

9702. The method of item 9612, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

9703. The method of item 9612, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

9704. The method of item 9612, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

9705. The method of item 9612, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

9706. The method of item 9612, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

9707. The method of item 9612, wherein the implant is further combinedwith an echogenic material.

9708. The method of item 9612, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

9709. The method of item 9612 wherein the device is sterilized.

9710. The method of item 9612 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

9711. The method of item 9612 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

9712. The method of item 9612 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

9713. The method of item 9612 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

9714. The method of item 9612 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

9715. The method of item 9612 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

9716. The method of item 9612 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

9717. The method of item 9612 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

9718. The method of item 9612 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

9719. The method of item 9612 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

9720. The method of item 9612 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

9721. The method of item 9612 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

9722. The method of item 9612 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

9723. The method of item 9612 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

9724. The method of item 9612 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

9725. The method of item 9612 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

9726. The method of item 9612 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

9727. The method of item 9612 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

9728. The method of item 9612 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

9729. The method of item 9612 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9730. The method of item 9612 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9731. The method of item 9612 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9732. The method of item 9612 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

9733. The method of item 9612 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9734. The method of item 9612 wherein the hernia mesh is made, in wholeor part, from synthetic fiber.

9735. The method of item 9612 wherein the hernia mesh comprisespolypropylene.

9736. A method of making a medical device comprising combining i) asurgical film implant, with ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

9737. The method of item 9736 wherein the fibrosing agent promotesregeneration.

9738. The method of item 9736 wherein the fibrosing agent promotesangiogenesis.

9739. The method of item 9736 wherein the fibrosing agent promotesfibroblast migration.

9740. The method of item 9736 wherein the fibrosing agent promotesfibroblast proliferation.

9741. The method of item 9736 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

9742. The method of item 9736 wherein the fibrosing agent promotestissue remodeling.

9743. The method of item 9736 wherein the fibrosing agent is an arterialvessel wall irritant.

9744. The method of item 9736 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9745. The method of item 9736 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9746. The method of item 9736 wherein the fibrosing agent is orcomprises silk.

9747. The method of item 9736 wherein the fibrosing agent is orcomprises mineral particles.

9748. The method of item 9736 wherein the fibrosing agent is orcomprises chitosan.

9749. The method of item 9736 wherein the fibrosing agent is orcomprises polylysine.

9750. The method of item 9736 wherein the fibrosing agent is orcomprises fibronectin.

9751. The method of item 9736 wherein the fibrosing agent is orcomprises bleomycin.

9752. The method of item 9736 wherein the fibrosing agent is orcomprises CTGF.

9753. The method of item 9736 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

9754. The method of item 9736 wherein the fibrosing agent is in the formof a particulate.

9755. The method of item 9736 wherein the composition further comprisesan inflammatory cytokine.

9756. The method of item 9736 wherein the composition further comprisesan agent that stimulates cell proliferation.

9757. The method of item 9736 wherein the composition is in the form ofa gel or paste.

9758. The method of item 9736 wherein the fibrosing agent is in the formof tufts.

9759. The method of item 9736 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9760. The method of item 9736 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9761. The method of item 9736, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

9762. The method of item 9736, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

9763. The method of item 9736, wherein the implant is combined with acoating, and the coating directly contacts the device.

9764. The method of item 9736, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

9765. The method of item 9736, wherein the implant is combined with acoating, and the coating partially covers the device.

9766. The method of item 9736, wherein the implant is combined with acoating, and the coating completely covers the device.

9767. The method of item 9736, wherein the implant is combined with acoating, and the coating is a uniform coating.

9768. The method of item 9736, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

9769. The method of item 9736, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

9770. The method of item 9736 wherein the implant is combined with acoating, and the coating is a patterned coating.

9771. The method of item 9736, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

9772. The method of item 9736, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

9773. The method of item 9736, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

9774. The method of item 9736, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

9775. The method of item 9736, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

9776. The method of item 9736, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

9777. The method of item 9736, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

9778. The method of item 9736, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

9779. The method of item 9736, wherein the implant is combined with acoating, and the coating further comprises a polymer.

9780. The method of item 9736, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

9781. The method of item 9736, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

9782. The method of item 9736, wherein the device comprises a polymer.

9783. The method of item 9736, wherein the device comprises a polymer,and the polymer is a component of the composition.

9784. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a copolymer.

9785. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

9786. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

9787. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

9788. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

9789. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

9790. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

9791. The method of item 9736, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

9792. The method of item 9736, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

9793. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

9794. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is an elastomer.

9795. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

9796. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

9797. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

9798. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

9799. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

9800. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a macromer.

9801. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

9802. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

9803. The method of item 9736, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

9804. The method of item 9736 wherein the fibrosing agent is locatedwithin pores or holes of the device.

9805. The method of item 9736 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

9806. The method of item 9736, wherein the implant is further combinedwith a second pharmaceutically active agent.

9807. The method of item 9736, wherein the implant is further combinedwith an anti-inflammatory agent.

9808. The method of item 9736 wherein the implant is further combinedwith an agent that inhibits infection.

9809. The method of item 9736, wherein the implant is further combinedwith an anthracycline.

9810. The method of item 9736, wherein the implant is further combinedwith doxorubicin.

9811. The method of item 9736, wherein the implant is further combinedwith mitoxantrone.

9812. The method of item 9736, wherein the implant is further combinedwith a fluoropyrimidine.

9813. The method of item 9736, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

9814. The method of item 9736, wherein the implant is further combinedwith a folic acid antagonist.

9815. The method of item 9736, wherein the implant is further combinedwith methotrexate.

9816. The method of item 9736, wherein the implant is further combinedwith a podophylotoxin.

9817. The method of item 9736, wherein the implant is further combinedwith etoposide.

9818. The method of item 9736 wherein the implant is further combinedwith a camptothecin.

9819. The method of item 9736, wherein the implant is further combinedwith a hydroxyurea.

9820. The method of item 9736, wherein the implant is further combinedwith a platinum complex.

9821. The method of item 9736, wherein the implant is further combinedwith cisplatin.

9822. The method of item 9736, wherein the implant is further combinedwith an anti-thrombotic agent.

9823. The method of item 9736, wherein the implant is further combinedwith a visualization agent.

9824. The method of item 9736, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

9825. The method of item 9736, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

9826. The method of item 9736, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

9827. The method of item 9736, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

9828. The method of item 9736, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

9829. The method of item 9736, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

9830. The method of item 9736, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

9831. The method of item 9736, wherein the implant is further combinedwith an echogenic material.

9832. The method of item 9736, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

9833. The method of item 9736 wherein the device is sterilized.

9834. The method of item 9736 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

9835. The method of item 9736 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

9836. The method of item 9736 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

9837. The method of item 9736 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

9838. The method of item 9736 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

9839. The method of item 9736 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

9840. The method of item 9736 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

9841. The method of item 9736 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

9842. The method of item 9736 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

9843. The method of item 9736 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

9844. The method of item 9736 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

9845. The method of item 9736 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

9846. The method of item 9736 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

9847. The method of item 9736 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

9848. The method of item 9736 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

9849. The method of item 9736 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

9850. The method of item 9736 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

9851. The method of item 9736 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

9852. The method of item 9736 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

9853. The method of item 9736 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9854. The method of item 9736 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9855. The method of item 9736 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9856. The method of item 9736 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

9857. The method of item 9736 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9858. The method of item 9736 wherein the surgical film implantcomprises cellulose or a cellulose derivative.

9859. The method of item 9736 wherein the surgical film implant isporous.

9860. The method of item 9736 wherein the surgical film implant isbiodegradable.

9861. A method of making a medical device comprising combining i) aspinal fusion implant, with ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

9862. The method of item 9861 wherein the fibrosing agent promotesregeneration.

9863. The method of item 9861 wherein the fibrosing agent promotesangiogenesis.

9864. The method of item 9861 wherein the fibrosing agent promotesfibroblast migration.

9865. The method of item 9861 wherein the fibrosing agent promotesfibroblast proliferation.

9866. The method of item 9861 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

9867. The method of item 9861 wherein the fibrosing agent promotestissue remodeling.

9868. The method of item 9861 wherein the fibrosing agent is an arterialvessel wall irritant.

9869. The method of item 9861 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9870. The method of item 9861 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9871. The method of item 9861 wherein the fibrosing agent is orcomprises silk.

9872. The method of item 9861 wherein the fibrosing agent is orcomprises mineral particles.

9873. The method of item 9861 wherein the fibrosing agent is orcomprises chitosan.

9874. The method of item 9861 wherein the fibrosing agent is orcomprises polylysine.

9875. The method of item 9861 wherein the fibrosing agent is orcomprises fibronectin.

9876. The method of item 9861 wherein the fibrosing agent is orcomprises bleomycin.

9877. The method of item 9861 wherein the fibrosing agent is orcomprises CTGF.

9878. The method of item 9861 wherein the fibrosing agent is in the formof a thread, or is in contact with a thread.

9879. The method of item 9861 wherein the fibrosing agent is in the formof a particulate.

9880. The method of item 9861 wherein the composition further comprisesan inflammatory cytokine.

9881. The method of item 9861 wherein the composition further comprisesan agent that stimulates cell proliferation.

9882. The method of item 9861 wherein the composition is in the form ofa gel or paste.

9883. The method of item 9861 wherein the fibrosing agent is in the formof tufts.

9884. The method of item 9861 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

9885. The method of item 9861 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

9886. The method of item 9861, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

9887. The method of item 9861, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

9888. The method of item 9861, wherein the implant is combined with acoating, and the coating directly contacts the device.

9889. The method of item 9861, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

9890. The method of item 9861, wherein the implant is combined with acoating, and the coating partially covers the device.

9891. The method of item 9861, wherein the implant is combined with acoating, and the coating completely covers the device.

9892. The method of item 9861, wherein the implant is combined with acoating, and the coating is a uniform coating.

9893. The method of item 9861, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

9894. The method of item 9861, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

9895. The method of item 9861 wherein the implant is combined with acoating, and the coating is a patterned coating.

9896. The method of item 9861, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

9897. The method of item 9861, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

9898. The method of item 9861, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

9899. The method of item 9861, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

9900. The method of item 9861, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

9901. The method of item 9861, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

9902. The method of item 9861, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

9903. The method of item 9861, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

9904. The method of item 9861, wherein the implant is combined with acoating, and the coating further comprises a polymer.

9905. The method of item 9861, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

9906. The method of item 9861, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

9907. The method of item 9861, wherein the device comprises a polymer.

9908. The method of item 9861, wherein the device comprises a polymer,and the polymer is a component of the composition.

9909. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a copolymer.

9910. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

9911. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

9912. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

9913. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

9914. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

9915. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

9916. The method of item 9861, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

9917. The method of item 9861, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

9918. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

9919. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is an elastomer.

9920. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

9921. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

9922. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

9923. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

9924. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

9925. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a macromer.

9926. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

9927. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

9928. The method of item 9861, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

9929. The method of item 9861 wherein the fibrosing agent is locatedwithin pores or holes of the device.

9930. The method of item 9861 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

9931. The method of item 9861, wherein the implant is further combinedwith a second pharmaceutically active agent.

9932. The method of item 9861, wherein the implant is further combinedwith an anti-inflammatory agent.

9933. The method of item 9861 wherein the implant is further combinedwith an agent that inhibits infection.

9934. The method of item 9861, wherein the implant is further combinedwith an anthracycline.

9935. The method of item 9861, wherein the implant is further combinedwith doxorubicin.

9936. The method of item 9861, wherein the implant is further combinedwith mitoxantrone.

9937. The method of item 9861, wherein the implant is further combinedwith a fluoropyrimidine.

9938. The method of item 9861, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

9939. The method of item 9861, wherein the implant is further combinedwith a folic acid antagonist.

9940. The method of item 9861, wherein the implant is further combinedwith methotrexate.

9941. The method of item 9861, wherein the implant is further combinedwith a podophylotoxin.

9942. The method of item 9861, wherein the implant is further combinedwith etoposide.

9943. The method of item 9861 wherein the implant is further combinedwith a camptothecin.

9944. The method of item 9861, wherein the implant is further combinedwith a hydroxyurea.

9945. The method of item 9861, wherein the implant is further combinedwith a platinum complex.

9946. The method of item 9861, wherein the implant is further combinedwith cisplatin.

9947. The method of item 9861, wherein the implant is further combinedwith an anti-thrombotic agent.

9948. The method of item 9861, wherein the implant is further combinedwith a visualization agent.

9949. The method of item 9861, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

9950. The method of item 9861, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

9951. The method of item 9861, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

9952. The method of item 9861, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

9953. The method of item 9861, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

9954. The method of item 9861, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

9955. The method of item 9861, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

9956. The method of item 9861, wherein the implant is further combinedwith an echogenic material.

9957. The method of item 986.1, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

9958. The method of item 9861 wherein the device is sterilized.

9959. The method of item 9861 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

9960. The method of item 9861 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

9961. The method of item 9861 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

9962. The method of item 9861 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

9963. The method of item 9861 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

9964. The method of item 9861 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year.

9965. The method of item 9861 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1 month to 6 months.

9966. The method of item 9861 wherein the fibrosing agent is released ineffective concentrations from the device over a period ranging fromabout 1-90 days.

9967. The method of item 9861 wherein the fibrosing agent is released ineffective concentrations from the device at a constant rate.

9968. The method of item 9861 wherein the fibrosing agent is released ineffective concentrations from the device at an increasing rate.

9969. The method of item 9861 wherein the fibrosing agent is released ineffective concentrations from the device at a decreasing rate.

9970. The method of item 9861 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by diffusion over a period ranging from the time of deployment ofthe device to about 90 days.

9971. The method of item 9861 wherein the fibrosing agent is released ineffective concentrations from the composition comprising the fibrosingagent by erosion of the composition over a period ranging from the timeof deployment of the device to about 90 days.

9972. The method of item 9861 wherein the device comprises about 0.01 μgto about 10 μg of the fibrosing agent.

9973. The method of item 9861 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

9974. The method of item 9861 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

9975. The method of item 9861 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

9976. The method of item 9861 wherein the device comprises about 1000 mgto about 2500 mg of the fibrosing agent.

9977. The method of item 9861 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

9978. The method of item 9861 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9979. The method of item 9861 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9980. The method of item 9861 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9981. The method of item 9861 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

9982. The method of item 9861 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

9983. The method of item 9861 wherein the spinal fusion device is afusion basket.

9984. The method of item 9861 wherein the spinal fusion device is afusion cage apparatus.

9985. The method of item 9861 wherein the spinal fusion device is aninterbody case.

9986. The method of item 9861 wherein the spinal fusion device is aninterbody implant.

9987. The method of item 9861 wherein the spinal fusion device is afusion cage anchoring device.

9988. The method of item 9861 wherein the spinal fusion device is afusion stabilization chamber.

9989. The method of item 9861 wherein the spinal fusion device is afusion cage anchoring plate.

9990. The method of item 9861 wherein the spinal fusion device is a bonefixation device.

9991. The method of item 9861 wherein the spinal fusion device is ananchoring bone plate.

9992. The method of item 9861 wherein the spinal fusion device is ananchoring bone screw.

9993. The method of item 9861 wherein the spinal fusion device is atissue filler.

9994. The method of item 9861 wherein the spinal fusion device is a bonecement.

9995. The method of item 9861 wherein the spinal fusion device is anallograft material.

9996. The method of item 9861 wherein the spinal fusion device is anautograft material.

9997. The method of item 9861 wherein the spinal fusion device is acollagen implant.

9998. The method of item 9861 wherein the spinal fusion device isinjectable.

9999. A method of making a medical device comprising combining i) aseptal occlusion patch implant, with ii) a fibrosing agent or acomposition comprising a fibrosing agent, where the fibrosing agentinduces a fibrotic response between the device and a patient in whichthe device is implanted.

10000. The method of item 9999 wherein the fibrosing agent promotesregeneration.

10001. The method of item 9999 wherein the fibrosing agent promotesangiogenesis.

10002. The method of item 9999 wherein the fibrosing agent promotesfibroblast migration.

10003. The method of item 9999 wherein the fibrosing agent promotesfibroblast proliferation.

10004. The method of item 9999 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

10005. The method of item 9999 wherein the fibrosing agent promotestissue remodeling.

10006. The method of item 9999 wherein the fibrosing agent is anarterial vessel wall irritant.

10007. The method of item 9999 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

10008. The method of item 9999 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

10009. The method of item 9999 wherein the fibrosing agent is orcomprises silk.

10010. The method of item 9999 wherein the fibrosing agent is orcomprises mineral particles.

10011. The method of item 9999 wherein the fibrosing agent is orcomprises chitosan.

10012. The method of item 9999 wherein the fibrosing agent is orcomprises polylysine.

10013. The method of item 9999 wherein the fibrosing agent is orcomprises fibronectin.

10014. The method of item 9999 wherein the fibrosing agent is orcomprises bleomycin.

10015. The method of item 9999 wherein the fibrosing agent is orcomprises CTGF.

10016. The method of item 9999 wherein the fibrosing agent is in theform of a thread, or is in contact with a thread.

10017. The method of item 9999 wherein the fibrosing agent is in theform of a particulate.

10018. The method of item 9999 wherein the composition further comprisesan inflammatory cytokine.

10019. The method of item 9999 wherein the composition further comprisesan agent that stimulates cell proliferation.

10020. The method of item 9999 wherein the composition is in the form ofa gel or paste.

10021. The method of item 9999 wherein the fibrosing agent is in theform of tufts.

10022. The method of item 9999 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

10023. The method of item 9999 wherein the device delivers the fibrosingagent locally to tissue proximate to the device.

10024. The method of item 9999, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

10025. The method of item 9999, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

10026. The method of item 9999, wherein the implant is combined with acoating, and the coating directly contacts the device.

10027. The method of item 9999, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

10028. The method of item 9999, wherein the implant is combined with acoating, and the coating partially covers the device.

10029. The method of item 9999, wherein the implant is combined with acoating, and the coating completely covers the device.

10030. The method of item 9999, wherein the implant is combined with acoating, and the coating is a uniform coating.

10031. The method of item 9999, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

10032. The method of item 9999, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

10033. The method of item 9999 wherein the implant is combined with acoating, and the coating is a patterned coating.

10034. The method of item 9999, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

10035. The method of item 9999, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

10036. The method of item 9999, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

10037. The method of item 9999, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

10038. The method of item 9999, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

10039. The method of item 9999, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

10040. The method of item 9999, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

10041. The method of item 9999, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

10042. The method of item 9999, wherein the implant is combined with acoating, and the coating further comprises a polymer.

10043. The method of item 9999, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

10044. The method of item 9999, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

10045. The method of item 9999, wherein the device comprises a polymer.

10046. The method of item 9999, wherein the device comprises a polymer,and the polymer is a component of the composition.

10047. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a copolymer.

10048. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

10049. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

10050. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

10051. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

10052. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

10053. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

10054. The method of item 9999, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

10055. The method of item 9999, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

10056. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

10057. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is an elastomer.

10058. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

10059. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

10060. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

10061. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

10062. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

10063. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a macromer.

10064. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

10065. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

10066. The method of item 9999, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

10067. The method of item 9999 wherein the fibrosing agent is locatedwithin pores or holes of the device.

10068. The method of item 9999 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

10069. The method of item 9999, wherein the implant is further combinedwith a second pharmaceutically active agent.

10070. The method of item 9999, wherein the implant is further combinedwith an anti-inflammatory agent.

10071. The method of item 9999 wherein the implant is further combinedwith an agent that inhibits infection.

10072. The method of item 9999, wherein the implant is further combinedwith an anthracycline.

10073. The method of item 9999, wherein the implant is further combinedwith doxorubicin.

10074. The method of item 9999, wherein the implant is further combinedwith mitoxantrone.

10075. The method of item 9999, wherein the implant is further combinedwith a fluoropyrimidine.

10076. The method of item 9999, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

10077. The method of item 9999, wherein the implant is further combinedwith a folic acid antagonist.

10078. The method of item 9999, wherein the implant is further combinedwith methotrexate.

10079. The method of item 9999, wherein the implant is further combinedwith a podophylotoxin.

10080. The method of item 9999, wherein the implant is further combinedwith etoposide.

10081. The method of item 9999 wherein the implant is further combinedwith a camptothecin.

10082. The method of item 9999, wherein the implant is further combinedwith a hydroxyurea.

10083. The method of item 9999, wherein the implant is further combinedwith a platinum complex.

10084. The method of item 9999, wherein the implant is further combinedwith cisplatin.

10085. The method of item 9999, wherein the implant is further combinedwith an anti-thrombotic agent.

10086. The method of item 9999, wherein the implant is further combinedwith a visualization agent.

10087. The method of item 9999, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

10088. The method of item 9999, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

10089. The method of item 9999, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

10090. The method of item 9999, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

10091. The method of item 9999, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

10092. The method of item 9999, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

10093. The method of item 9999, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

10094. The method of item 9999, wherein the implant is further combinedwith an echogenic material.

10095. The method of item 9999, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

10096. The method of item 9999 wherein the device is sterilized.

10097. The method of item 9999 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

10098. The method of item 9999 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein

-   the tissue is connective tissue.

10099. The method of item 9999 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

10100. The method of item 9999 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

10101. The method of item 9999 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

10102. The method of item 9999 wherein the fibrosing agent is releasedin effective concentrations from the device over a period ranging fromthe time of deployment of the device to about 1 year.

10103. The method of item 9999 wherein the fibrosing agent is releasedin effective concentrations from the device over a period ranging fromabout 1 month to 6 months.

10104. The method of item 9999 wherein the fibrosing agent is releasedin effective concentrations from the device over a period ranging fromabout 1-90 days.

10105. The method of item 9999 wherein the fibrosing agent is releasedin effective concentrations from the device at a constant rate.

10106. The method of item 9999 wherein the fibrosing agent is releasedin effective concentrations from the device at an increasing rate.

10107. The method of item 9999 wherein the fibrosing agent is releasedin effective concentrations from the device at a decreasing rate.

10108. The method of item 9999 wherein the fibrosing agent is releasedin effective concentrations from the composition comprising thefibrosing agent by diffusion over a period ranging from the time ofdeployment of the device to about 90 days.

10109. The method of item 9999 wherein the fibrosing agent is releasedin effective concentrations from the composition comprising thefibrosing agent by erosion of the composition over a period ranging fromthe time of deployment of the device to about 90 days.

10110. The method of item 9999 wherein the device comprises about 0.01μg to about 10 μg of the fibrosing agent.

10111. The method of item 9999 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

10112. The method of item 9999 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

10113. The method of item 9999 wherein the device comprises about 250 mgto about 1000 mg of the fibrosing agent.

10114. The method of item 9999 wherein the device comprises about 1000mg to about 2500 mg of the fibrosing agent.

10115. The method of item 9999 wherein a surface of the device comprisesless than 0.01 μg of the fibrosing agent per mm² of device surface towhich the fibrosing agent is applied.

10116. The method of item 9999 wherein a surface of the device comprisesabout 0.01 μg to about 1 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

10117. The method of item 9999 wherein a surface of the device comprisesabout 1 μg to about 10 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

10118. The method of item 9999 wherein a surface of the device comprisesabout 10 μg to about 250 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

10119. The method of item 9999 wherein a surface of the device comprisesabout 250 μg to about 1000 μg of the fibrosing agent of fibrosing agentper mm² of device surface to which the fibrosing agent is applied.

10120. The method of item 9999 wherein a surface of the device comprisesabout 1000 μg to about 2500 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

10121. The method of item 9999 wherein the septal occlusion patch is aseptal closure device.

10122. The method of item 9999 wherein the septal occlusion patch is ashunt closure device.

10123. The method of item 9999 wherein the septal occlusion patch is anintracardiac occluder.

10124. The method of item 9999 wherein the septal occlusion patch is adefect occluding system.

10125. The method of item 9999 wherein the septal occlusion patch is anintravascular shunt device.

10126. A method of making a medical device comprising combining i) anendoluminal fastener implant with ii) a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.

10127. The method of item 10126 wherein the fibrosing agent promotesregeneration.

10128. The method of item 10126 wherein the fibrosing agent promotesangiogenesis.

10129. The method of item 10126 wherein the fibrosing agent promotesfibroblast migration.

10130. The method of item 10126 wherein the fibrosing agent promotesfibroblast proliferation.

10131. The method of item 10126 wherein the fibrosing agent promotesdeposition of extracellular matrix (ECM).

10132. The method of item 10126 wherein the fibrosing agent promotestissue remodeling.

10133. The method of item 10126 wherein the fibrosing agent is anarterial vessel wall irritant.

10134. The method of item 10126 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

10135. The method of item 10126 wherein the device delivers thefibrosing agent locally to tissue proximate to the device.

10136. The method of item 10126 wherein the fibrosing agent is orcomprises silk.

10137. The method of item 10126 wherein the fibrosing agent is orcomprises mineral particles.

10138. The method of item 10126 wherein the fibrosing agent is orcomprises chitosan.

10139. The method of item 10126 wherein the fibrosing agent is orcomprises polylysine.

10140. The method of item 10126 wherein the fibrosing agent is orcomprises fibronectin.

10141. The method of item 10126 wherein the fibrosing agent is orcomprises bleomycin.

10142. The method of item 10126 wherein the fibrosing agent is orcomprises CTGF.

10143. The method of item 10126 wherein the fibrosing agent is in theform of a thread, or is in contact with a thread.

10144. The method of item 10126 wherein the fibrosing agent is in theform of a particulate.

10145. The method of item 10126 wherein the composition furthercomprises an inflammatory cytokine.

10146. The method of item 10126 wherein the composition furthercomprises an agent that stimulates cell proliferation.

10147. The method of item 10126 wherein the composition is in the formof a gel or paste.

10148. The method of item 10126 wherein the fibrosing agent is in theform of tufts.

10149. The method of item 10126 wherein the fibrosing agent promotesadhesion between the device and a host into which the device isimplanted.

10150. The method of item 10126 wherein the device delivers thefibrosing agent locally to tissue proximate to the device.

10151. The method of item 10126, wherein the implant is combined with acoating, and the coating comprises the fibrosing agent.

10152. The method of item 10126, wherein the implant is combined with acoating, and the coating is disposed on a surface of the device.

10153. The method of item 10126, wherein the implant is combined with acoating, and the coating directly contacts the device.

10154. The method of item 10126, wherein the implant is combined with acoating, and the coating indirectly contacts the device.

10155. The method of item 10126, wherein the implant is combined with acoating, and the coating partially covers the device.

10156. The method of item 10126, wherein the implant is combined with acoating, and the coating completely covers the device.

10157. The method of item 10126, wherein the implant is combined with acoating, and the coating is a uniform coating.

10158. The method of item 10126, wherein the implant is combined with acoating, and the coating is a non-uniform coating.

10159. The method of item 10126, wherein the implant is combined with acoating, and the coating is a discontinuous coating.

10160. The method of item 10126 wherein the implant is combined with acoating, and the coating is a patterned coating.

10161. The method of item 10126, wherein the implant is combined with acoating, and the coating has a thickness of 100 μm or less.

10162. The method of item 10126, wherein the implant is combined with acoating, and the coating has a thickness of 10 μm or less.

10163. The method of item 10126, wherein the implant is combined with acoating, and the coating adheres to the surface of the device upondeployment of the device.

10164. The method of item 10126, wherein the implant is combined with acoating, and the coating is stable at room temperature for a period ofat least 1 year.

10165. The method of item 10126, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 0.0001% to about 1% by weight.

10166. The method of item 10126, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 1% to about 10% by weight.

10167. The method of item 10126, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 10% to about 25% by weight.

10168. The method of item 10126, wherein the implant is combined with acoating, and the fibrosing agent is present in the coating in an amountranging between about 25% to about 70% by weight.

10169. The method of item 10126, wherein the implant is combined with acoating, and the coating further comprises a polymer.

10170. The method of item 10126, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition.

10171. The method of item 10126, wherein the device comprises a firstcoating having a first composition and a second coating having a secondcomposition, where the first composition and the second composition aredifferent.

10172. The method of item 10126, wherein the device comprises a polymer.

10173. The method of item 10126, wherein the device comprises a polymer,and the polymer is a component of the composition.

10174. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a copolymer.

10175. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a block copolymer.

10176. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a random copolymer.

10177. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a biodegradable polymer.

10178. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a non-biodegradable polymer.

10179. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a hydrophilic polymer.

10180. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a hydrophobic polymer.

10181. The method of item 10126, wherein the implant is combined with apolymer, and the polymer has hydrophilic domains.

10182. The method of item 10126, wherein the implant is combined with apolymer, and the polymer has hydrophobic domains.

10183. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a non-conductive polymer.

10184. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is an elastomer.

10185. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a hydrogel.

10186. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a silicone polymer.

10187. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a hydrocarbon polymer.

10188. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a styrene-derived polymer.

10189. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a butadiene polymer.

10190. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a macromer.

10191. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a poly(ethylene glycol) polymer.

10192. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is an amorphous polymer.

10193. The method of item 10126, wherein the implant is combined with apolymer, and the polymer is a lubricious coating.

10194. The method of item 10126 wherein the fibrosing agent is locatedwithin pores or holes of the device.

10195. The method of item 10126 wherein the fibrosing agent is locatedwithin a channel, lumen, or divet of the device.

10196. The method of item 10126, wherein the implant is further combinedwith a second pharmaceutically active agent.

10197. The method of item 10126, wherein the implant is further combinedwith an anti-inflammatory agent.

10198. The method of item 10126 wherein the implant is further combinedwith an agent that inhibits infection.

10199. The method of item 10126, wherein the implant is further combinedwith an anthracycline.

10200. The method of item 10126, wherein the implant is further combinedwith doxorubicin.

10201. The method of item 10126, wherein the implant is further combinedwith mitoxantrone.

10202. The method of item 10126, wherein the implant is further combinedwith a fluoropyrimidine.

10203. The method of item 10126, wherein the implant is further combinedwith 5-fluorouracil (5-FU).

10204. The method of item 10126, wherein the implant is further combinedwith a folic acid antagonist.

10205. The method of item 10126, wherein the implant is further combinedwith methotrexate.

10206. The method of item 10126, wherein the implant is further combinedwith a podophylotoxin.

10207. The method of item 10126, wherein the implant is further combinedwith etoposide.

10208. The method of item 10126 wherein the implant is further combinedwith a camptothecin.

10209. The method of item 10126, wherein the implant is further combinedwith a hydroxyurea.

10210. The method of item 10126, wherein the implant is further combinedwith a platinum complex.

10211. The method of item 10126, wherein the implant is further combinedwith cisplatin.

10212. The method of item 10126, wherein the implant is further combinedwith an anti-thrombotic agent.

10213. The method of item 10126, wherein the implant is further combinedwith a visualization agent.

10214. The method of item 10126, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises a metal,a halogenated compound, or a barium containing compound.

10215. The method of item 10126, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is aradiopaque material, wherein the radiopaque material comprises barium,tantalum, or technetium.

10216. The method of item 10126, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent is a MRIresponsive material.

10217. The method of item 10126, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises agadolinium chelate.

10218. The method of item 10126, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprisesiron, magnesium, manganese, copper, or chromium.

10219. The method of item 10126, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises aniron oxide compound.

10220. The method of item 10126, wherein the implant is further combinedwith a visualization agent, wherein the visualization agent comprises adye, pigment, or colorant.

10221. The method of item 10126, wherein the implant is further combinedwith an echogenic material.

10222. The method of item 10126, wherein the implant is further combinedwith an echogenic material, and the echogenic material is in the form ofa coating.

10223. The method of item 10126 wherein the device is sterilized.

10224. The method of item 10126 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice.

10225. The method of item 10126 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is connective tissue.

10226. The method of item 10126 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is muscle tissue.

10227. The method of item 10126 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is nerve tissue.

10228. The method of item 10126 wherein the fibrosing agent is releasedinto tissue in the vicinity of the device after deployment of thedevice, wherein the tissue is epithelium tissue.

10229. The method of item 10126 wherein the fibrosing agent is releasedin effective concentrations from the device over a period ranging fromthe time of deployment of the device to about 1 year.

10230. The method of item 10126 wherein the fibrosing agent is releasedin effective concentrations from the device over a period ranging fromabout 1 month to 6 months.

10231. The method of item 10126 wherein the fibrosing agent is releasedin effective concentrations from the device over a period ranging fromabout 1-90 days.

10232. The method of item 10126 wherein the fibrosing agent is releasedin effective concentrations from the device at a constant rate.

10233. The method of item 10126 wherein the fibrosing agent is releasedin effective concentrations from the device at an increasing rate.

10234. The method of item 10126 wherein the fibrosing agent is releasedin effective concentrations from the device at a decreasing rate.

10235. The method of item 10126 wherein the fibrosing agent is releasedin effective concentrations from the composition comprising thefibrosing agent by diffusion over a period ranging from the time ofdeployment of the device to about 90 days.

10236. The method of item 10126 wherein the fibrosing agent is releasedin effective concentrations from the composition comprising thefibrosing agent by erosion of the composition over a period ranging fromthe time of deployment of the device to about 90 days.

10237. The method of item 10126 wherein the device comprises about 0.01μg to about 10 μg of the fibrosing agent.

10238. The method of item 10126 wherein the device comprises about 10 μgto about 10 mg of the fibrosing agent.

10239. The method of item 10126 wherein the device comprises about 10 mgto about 250 mg of the fibrosing agent.

10240. The method of item 10126 wherein the device comprises about 250mg to about 1000 mg of the fibrosing agent.

10241. The method of item 10126 wherein the device comprises about 1000mg to about 2500 mg of the fibrosing agent.

10242. The method of item 10126 wherein a surface of the devicecomprises less than 0.01 μg of the fibrosing agent per mm² of devicesurface to which the fibrosing agent is applied.

10243. The method of item 10126 wherein a surface of the devicecomprises about 0.01 μg to about 1 μg of the fibrosing agent per mm² ofdevice surface to which the fibrosing agent is applied.

10244. The method of item 10126 wherein a surface of the devicecomprises about 1 μg to about 10 μg of the fibrosing agent per mm² ofdevice surface to which the fibrosing agent is applied.

10245. The method of item 10126 wherein a surface of the devicecomprises about 10 μg to about 250 μg of the fibrosing agent per mm² ofdevice surface to which the fibrosing agent is applied.

10246. The method of item 10126 wherein a surface of the devicecomprises about 250 μg to about 1000 μg of the fibrosing agent offibrosing agent per mm² of device surface to which the fibrosing agentis applied.

10247. The method of item 10126 wherein a surface of the devicecomprises about 1000 μg to about 2500 μg of the fibrosing agent per mm²of device surface to which the fibrosing agent is applied.

The following examples are offered by way of illustration, and not byway of limitation.

EXAMPLES Example 1 Coating of Medical Implants with Fibronectin

The coating apparatus consisted of an overhead stirrer (FisherScientific) orientated horizontally. A conical stainless steel head isattached to the revolving chuck of the stirrer. One end of an aneurysmcoil is pulled up onto the conical head until held firmly. The other endis attached to a clip-swivel device that holds the medical implant in ahorizontal position, but allowed the medical implant to rotate along itsaxis. The stirrer is then set to rotate at 30 rpm so that the wholemedical implant rotates along the horizontal axis at this speed. A 1%(w/w) fibronectin (Calbiochem, San Diego, Calif.) solution in sterilewater is prepared. Two hundred microliters of this solution is slowlypipetted as a 3 mm wide ring located 5 mm from the end of the medicalimplant fixed in the conical steel head over a period of 2 minutes asthe medical implant rotates. The fibronectin is then dried under astream of nitrogen as the medical implant continues to rotate. When dry,the medical implant is removed, turned around and the other end of themedical implant coated in the same manner. Using this method a flexiblering of fibronectin is deposited on both ends of the medical implantwithout compromise of the physical characteristics of the medicalimplant. Other examples of medical implants that may be coated in asimilar fashion include vascular (vaso-) occlusive coils and vascular(vaso-) occlusion implants.

Example 2 Coating of Medical Implants with Poly-L-Lysine

A medical implant is coated using the procedure described in Example 1.A 1% (w/w) poly-L-lysine (Sigma, St. Louis, Mo.) solution in sterilewater is prepared. Two hundred microliters of this solution is slowlypipetted as a 3 mm wide ring located 5 mm from the end of the medicalimplant fixed in the conical steel head over a period of 2 minutes asthe medical implant rotates. The poly-L-lysine is then dried under astream of nitrogen as the medical implant continues to rotate. When dry,the medical implant is removed, turned around and the other end of themedical implant coated in the same manner. Using this method a flexiblering of poly-L-Lysine is deposited on both ends of the medical implantwithout compromise of the physical characteristics of the medicalimplant.

Example 3 Coating of Medical Implants with N-Carboxybutyl Chitosan

A medical implant is coated using the procedure described in Example 1.A 1% (w/w) n-carboxybutyl chitosan (Carbomer, Westborough, Mass.)solution in sterile water is prepared. Two hundred microliters of thissolution is slowly pipetted as a 3 mm wide ring located 5 mm from theend of the medical implant fixed in the conical steel head over a periodof 2 minutes as the medical implant rotates. The n-carboxybutyl chitosanis dried under a stream of nitrogen as the medical implant continues torotate. When dry, the medical implant is removed, turned around and theother end coated in the same manner. Using this method a flexible ringof n-carboxybutyl chitosan is deposited on both ends of the medicalimplant without compromise of the physical characteristics of themedical implant.

Example 4 Coating of Medical Implants with Bromocriptine InPoly(Ethylene Vinyl Acetate)

A medical implant is coated using the procedure described in Example 1.A 4.5% w/w solution of EVA (60/40 ratio ethylene to vinyl acetate)(Polysciences USA) is prepared in dichloromethane. Bromocriptinemesylate (Sigma, St. Louis, Mo.) is dissolved/suspended in this solutionat 5 mg/ml. Two hundred microliters of this solution is slowly pipettedas a 3 mm wide ring located 5 mm from the end of the medical implantfixed in the conical steel head over a period of 2 minutes as themedical implant rotates. The EVA/bromocriptine is dried under a streamof nitrogen as the medical implant continues to rotate. When dry, themedical implant is removed, turned around and the other end of themedical implant coated in the same manner. Using this method a flexiblering of EVA/bromocriptine is deposited on both ends of the medicalimplant without compromise of the physical characteristics of themedical implant.

Example 5 Preparation of Inflammatory Microcrystals (Monosodium UrateMonohydrate and Calcium Pyrophosphate Dihydrate)

Monosodium urate monohydrate (MSUM) microcrystals were grown. A solutionof uric acid and sodium hydroxide at 55° C. and pH 8.9 was left to standovernight at room temperature. The crystals were rinsed several timeswith cold (4° C.) distilled water and dried at 60° C. for 12 hours in acirculating hot-air oven (Fisher, Isotemp).

Triclinic calcium pyrophosphate dihydrate (CPPD) crystals were preparedas follows. A 250 ml beaker containing 103 ml distilled water was heatedin a water bath to 60° C., and stirred constantly with a TEFLON-coatedstir bar. The stirring was slowed and 0.71 ml of concentratedhydrochloric acid and 0.32 ml of glacial acetic acid were added,followed by 0.6 g of calcium acetate. A 150 ml beaker containing 20 mldistilled water was heated to 60° C. in the water bath, and 0.6 gcalcium acetate added. The rate of stir was increased in the 250 mlbeaker, and 2 g of calcium acid pyrophosphate added rapidly. When theCaH₂P₂O₇ had nearly all dissolved, the rate of stirring was reduced for5 minutes, then over a period of 15 seconds, the contents of the smallbeaker were poured into the large beaker with vigorous stirring. In thepreparation of subsequent batches, a minute amount of triclinic CPPDcrystals was added to the large beaker as seed material. Stirring wasdiscontinued, leaving a white gel. This was allowed to remainundisturbed in the cooling water bath. The pH of the supernatant wasalways less than 3.0. The gel collapsed as CPPD crystals formed in 24hours. The crystals were washed in distilled water 3 times, washed inethanol then acetone, and air dried.

Example 6 Coating of Medical Implants with Inflammatory Microcrystals(Monosodium Urate Monohydrate or Calcium Pyrophosphate Dihydrate)

A medical implant is coated according to the procedure described inExample 1. A 4.5% w/w solution of EVA (60/40 ratio ethylene to vinylacetate) (Polysciences) is prepared in dichloromethane. Inflammatorymicrocrystals (MSUM or CPPD) are ground in a pestle and mortar to aparticle size of 10 to 50 micrometers and suspended in the solution at 5mg/ml. Two hundred microliters of this suspension is slowly pipetted asa 3 mm wide ring located 5 mm from the end of the medical implant fixedin the conical steel head over a period of 2 minutes as the medicalimplant rotates. The EVA/microcrystal coating is then dried under astream of nitrogen as the medical implant continues to rotate. When dry,the medical implant is removed, turned around and the other end of themedical implant coated in the same manner. Using this method a flexiblering of EVA/microcrystals is deposited on both ends of the medicalimplant without compromise of the physical characteristics of themedical implant.

Example 7 Coating of Medical Implants with Inflammatory Microcrystals(Monosodium Urate Monohydrate or Calcium Pyrophosphate Dihydrate)

A 1% w/w solution of medical grade polyurethane (PU) (Thermomedics,Woburn, Mass.) is prepared in dichloromethane. Inflammatorymicrocrystals (CPPD or MSUM) are ground in a pestle and mortar to aparticle size of 10 to 50 micrometers and suspended in the solution at 2mg/ml. Immediately prior to surgical insertion each end of a medicalimplant (e.g., aneurysm coil or hernia mesh) is inserted into the shakensuspension to a depth of approximately 5 mm for 2 seconds. The medicalimplant is air-dried (gently rotated by hand for 3 minutes). Using thismethod a flexible ring of coating of EVA/microcrystals is deposited onboth ends of the medical implant without compromise of the physicalcharacteristics of the medical implant.

Example 8 Coating of Medical Implants with Bromocriptine in Polyurethane

A 1% w/w solution of medical grade polyurethane (PU) (Thermomedics) isprepared in dichloromethane. Bromocriptine mesylate (Sigma) at 5% w/w toPU is dissolved/suspended in this solution. The solution is placed in a5 ml Fisher TLC atomizer (Fisher Scientific). Prior to surgery themedical implant is suspended vertically in a fume hood and 1 ml of thesolution sprayed (using nitrogen propellant) onto the bottom 1 cm of themedical implant by revolving the medical implant through 360 degrees.The medical implant is dried for 2 minutes and then the other end of themedical implant is sprayed in a similar manner. The medical implant isthen further air dried (gently rotated by hand for 3 minutes). Usingthis method a flexible ring of bromocriptine/PU is deposited on bothends of the medical implant without compromise of the physicalcharacteristics of the medical implant. It is envisaged that ultimatelya bromocriptine/PU solution in DCM may be available to the surgeon inthe form of a small aerosol can for the above procedure.

Example 9 Coating of Medical Implants with Inflammatory Microcrystals(Monosodium Urate Monohydrate or Calcium Pyrophosphate Dihydrate)

A medical implant is coated according to the procedure described inExample 1. A 4.5% w/w solution of poly(lactide co-glycolide) (85:15) (IV0.61) (Birmingham Polymers, Birmingham, Ala.) blended withmethoxypolyethylene glycol 350 (MePEG 350) (Union Carbide, Danbury,Conn.) in a ratio of 80:20 w/w (PLGA:MePEG) is prepared indichloromethane. Inflammatory microcrystals are suspended in thesolution at 5 mg/ml. Two hundred microliters of this suspension isslowly pipetted as a 3 mm wide ring located 5 mm from the end of themedical implant fixed in the conical steel head over a period of 2minutes as the medical implant rotates. The PLGA/MePEG/inflammatorycrystals are then dried under a stream of nitrogen as the medicalimplant continues to rotate. When dry, the medical implant is removed,turned around and the other end of the medical implant coated in thesame manner. Using this method a flexible ring ofPLGA/MePEG/microcrystals is deposited on both ends of the medicalimplant without compromise of the physical characteristics of themedical implant.

Example 10 Coating of Medical Implants with Angiotensin 2 Encapsulatedin Polyethylene Glycol (PEG)

1.8 grams of polyethylene glycol (PEG 1475) (Union Carbide) is placed ina flat-bottomed 20 ml glass scintillation vial and warmed to 50° C. tomelt the PEG in a water bath, 200 mg of glycerol (Fisher Scientific) isadded. 2 mg of angiotensin 2 (Sigma) is weighed into the vial andblended/dissolved into the melted PEG at 50° C. The vial is angled at 10degrees in a water bath by use of a clamp. Each end of a medical implant(e.g., aneurysm coil or hernia mesh) is dipped rotated into the moltenformulation, so that a ring of that a coating of the material isdeposited on the bottom 5 mm of the exterior surface of the medicalimplant. The medical implant is then cooled and stored at 4° C. untiluse. Alternatively, to enable dipping immediately prior to surgery thePEG/angiotensin mixture is stored at 4° C. until use. Immediately priorto surgery, the vial of PEG/angiotensin is warmed to 50° C. for 2minutes to melt and the medical implant is coated as described above.

Example 11 Coating of Medical Implants with Transforming Growth Factor-9(TGF-9) in Crosslinked Hyaluronic Acid

A medical implant is coated according to the procedure described inExample 1. A 1% solution of hyaluronic acid (HA) (Sodium salt, Sigma) inwater, containing 30% glycerol (w/w to HA) (Fisher Scientific) and 8 mM1-ethyl-3-(−3 dimethylaminopropyl)carbodiimide (EDAC) is prepared bydissolution overnight. TGF-9 (Calbiochem, San Diego, Calif.) isdissolved at 0.01 mg/ml in this solution. Two hundred microliters ofthis solution is slowly pipetted as a 3 mm wide ring located 5 mm fromthe end of the medical implant fixed in the conical steel head over aperiod of 2 minutes as the medical implant rotates. TheHA/glycerol/TGF-9 solution is dried under a stream of nitrogen as themedical implant continues to rotate. When dry, the medical implant isremoved, turned around and the other end coated in the same manner.Using this method a flexible ring of HA/glycerol/TGF-9 is deposited onboth ends of the medical implant without compromise of the physicalcharacteristics of the medical implant.

Example 12 Coating of Medical Implants with Fibroblast Growth Factor(FGF) in Crosslinked Chitosan

A medical implant is coated according to the procedure described inExample 1. A 1% solution of chitosan (Medical grade, Carbomer,Westborough, Mass.) in dilute acetic acid (pH 5), containing 30%glycerol (w/w to chitosan) (Fisher Scientific) and 0.5% glutaraldehyde(Sigma, St. Louis, Mo.) is prepared by dissolution overnight. FGF(Calbiochem, San Diego, Calif.) is dissolved at 0.01 mg/ml in thissolution. Two hundred microliters of this solution is slowly pipetted asa 3 mm wide ring located 5 mm from the end of the medical implant fixedin the conical steel head over a period of 2 minutes as the medicalimplant rotates. The chitosan/glycerol/FGF solution is dried under astream of nitrogen as the medical implant continues to rotate. When dry,the medical implant is removed, turned around and the other end coatedin the same manner. Using this method a flexible ring ofchitosan/glycerol/FGF is deposited on both ends of the medical implantwithout compromise of the physical characteristics of the medicalimplant.

Example 13 Screening Procedure for Assessment of Perigraft Reaction

A rabbit perivascular model is described for identifying arterial vesselwall irritants. Large domestic rabbits are placed under generalanesthetic. Using aseptic precautions, the infrarenal abdominal aorta isexposed and clamped at its superior and inferior aspects. A longitudinalarterial wall arteriotomy is performed and a 2 millimeter diameter, 1centimeter long segment of PTFE graft is inserted within the aorta andthe proximal and distal aspect of the graft is sewn so that the entireaortic blood flow is through the graft which is contained in theabdominal aorta in the manner of open surgical abdominal aortic repairin humans (except that no aneurysm is present in this model). Theaortotomy is then surgically closed and the abdominal wound closed andthe animal recovered.

The animals are randomized to receive standard PTFE grafts or grafts ofwhich the middle 1 cm is coated alone circumferentially with nothing(control), or with an agent that induces a vessel wall reaction oradhesion between a stent graft and vessel wall alone or contained in aslow release, polymer such as polycaprolactone or polylactic acid.

The animals are sacrificed between 1 and 6 weeks post surgery, the aortais removed en bloc and the area in relation to the graft is grosslyexamined for adhesive reaction. Any difference in morphology orhistology of the vessel wall from portions of the artery which containno graft, portion which contain graft without coating, and portion whichcontained graft with coating is noted.

Example 14 Animal Abdominal Aortic Aneurysm Model

An animal model is described for determining whether a stent graftcontaining a biologically active or irritative substance stimulatesfibrosis. Pigs or sheep are placed under general anesthetic. Usingaseptic precautions the abdominal aorta is exposed. The animal isheparinized and the aorta is cross clamped below the renal arteries andabove the bifurcation. Collaterals are temporarily controlled withvessel loops or clips that are removed upon completion of the procedure.A longitudinal aortotomy is created in the arterial aspect of the aorta,and an elliptical shaped patch of rectus sheath from the same animal issutured into the aortotomy to create an aneurysm. The aortic clamps fromthe lumbar arteries and collaterals are removed and the abdomen closed.After 30 days, the animal is reanesthesized and the abdominal wall againopened. A cutdown is performed on the iliac artery and through this, astent graft is positioned across the infrarenal abdominal aorta aneurysmextending from normal infrarenal abdominal aorta above to normalinfrarenal abdominal aorta below the surgically created aneurysm and thedevice is released in a conventional way.

Animals are randomized into groups of 5 receiving uncoated stent grafts,stent graft containing slow release polymer alone, and stent graftcontaining a biologically active or irritative substance as determinedby the previously mentioned screening exam. After closure of thearteriotomy and of the abdominal wound, the animal is allowed torecover. At 6 weeks and 3 months post stent graft insertion, the animalis sacrificed and the aorta removed en bloc. The infrarenal abdominalaorta is examined for evidence of histologic reaction and perigraftleaking.

Example 15 Screening Assay for Assessing the Effect of Cyclosporine a onCell Proliferation

An in vitro assay is described for determining whether a substancestimulates cell (fibroblast) proliferation (see, In Vitro Toxicol.(1990) 3: 219; Biotech. Histochem. (1993) 68: 29; Anal. Biochem. (1993)213: 426). Smooth muscle cells at 70-90% confluency are trypsinized,replated at 600 cells/well in media in 96-well plates and allowed toattachment overnight. Cyclosporine A is prepared in DMSO at aconcentration of 10⁻² M and diluted 10-fold to give a range of stockconcentrations (10⁻⁸ M to 10⁻² M). Drug dilutions are diluted 1/1000 inmedia and added to cells to give a total volume of 200 μL/well. Eachdrug concentration is tested in triplicate wells. Plates containingsmooth muscle cells and cyclosporine A are incubated at 37° C. for 72hours.

To terminate the assay, the media is removed by gentle aspiration. A1/400 dilution of CYQUANT 400×GR dye indicator (Molecular Probes;Eugene, Oreg.) is added to 1× cell lysis buffer, and 200 μL of themixture is added to the wells of the plate. Plates are incubated at roomtemperature, protected from light for 3-5 minutes. Fluorescence is readin a fluorescence microplate reader at −480 nm excitation wavelength and˜520 nm emission maxima. Activation of proliferation is determined bytaking the average of triplicate wells and comparing average relativefluorescence units to the DMSO control (see FIG. 1).

The assay was repeated for the following proliferative therapeuticagents: dexamethasone (FIG. 2), all-trans retinoic acid (FIG. 3),isotretinoin (FIG. 4), 17-β-estradiol (FIG. 5), and1a,25-dihydroxy-vitamin D₃ (FIG. 6).

Example 16 Screening Assay for Assessing the Effect of PDGF on SmoothMuscle Cell Migration

An in vitro assay is described for determining whether a substancestimulates cell (fibroblast) migration. Primary human smooth musclecells are starved of serum in smooth muscle cell basal media containinginsulin and human basic fibroblast growth factor (bFGF) for 16 hoursprior to the assay. For the migration assay, cells are trypsinized toremove cells from flasks, washed with migration media and diluted to aconcentration of 2-2.5×10⁵ cells/ml in migration media. Migration mediaconsists of phenol red free Dulbecco's Modified Eagle Medium (DMEM)containing 0.35% human serum albumin. A 100 μL volume of smooth musclecells (approximately 20,000-25,000 cells) is added to the top of aBoyden chamber assembly (Chemicon QCM CHEMOTAXIS 96-well migrationplate). To the bottom wells, the chemotactic agent, recombinant humanplatelet derived growth factor (rhPDGF-BB) is added at a concentrationof 10 ng/ml in a total volume of 150 μL. Paclitaxel is prepared in DMSOat a concentration of 10⁻² M and serially diluted 10-fold to give arange of stock concentrations (10⁻⁸ M to 10⁻² M). Paclitaxel is added tocells by directly adding paclitaxel DMSO stock solutions, preparedearlier, at a 1/1000 dilution, to the cells in the top chamber. Platesare incubated for 4 hours to allow cell migration.

At the end of the 4 hour period, cells in the top chamber are discardedand the smooth muscle cells attached to the underside of the filter aredetached for 30 minutes at 37° C. in Cell Detachment Solution(Chemicon). Dislodged cells are lysed in lysis buffer containing the DNAbinding CYQUANT GR dye and incubated at room temperature for 15 minutes.Fluorescence is read in a fluorescence microplate reader at ˜480 nmexcitation wavelength and ˜520 nm emission maxima. Relative fluorescenceunits from triplicate wells are averaged after subtracting backgroundfluorescence (control chamber without chemoattractant) and averagenumber of cells migrating is obtained from a standard curve of smoothmuscle cells serially diluted from 25,000 cells/well down to 98cells/well. Inhibitory concentration of 50% (IC₅₀) is determined bycomparing the average number of cells migrating in the presence ofpaclitaxel to the positive control (smooth muscle cell chemotaxis inresponse to rhPDGF-BB). See FIG. 7. References: Biotechniques (2000) 29:81; J. Immunol Methods (2001) 254: 85.

Example 17 In Vivo Evaluation of Silk Coated Perivascular Pu Films toAssess Scarring

A rat carotid artery model is described for determining whether asubstance stimulates fibrosis. Wistar rats weighing 300 g to 400 g areanesthetized with halothane. The skin over the neck region is shaved andthe skin is sterilized. A vertical incision is made over the trachea andthe left carotid artery is exposed. A polyurethane film covered withsilk strands or a control uncoated PU film is wrapped around a distalsegment of the common carotid artery. The wound is closed and the animalis recovered. After 28 days, the rats are sacrificed with carbon dioxideand pressure-perfused at 100 mmHg with 10% buffered formaldehyde. Bothcarotid arteries are harvested and processed for histology. Serialcross-sections can be cut every 2 mm in the treated left carotid arteryand at corresponding levels in the untreated right carotid artery.Sections are stained with H&E and Movat's stains to evaluate tissuegrowth around the carotid artery. Area of perivascular granulationtissue is quantified by computer-assisted morphometric analysis. Area ofthe granulation tissue is significantly higher in the silk coated groupthan in the control uncoated group. See FIG. 8.

Example 18 In Vivo Evaluation of Perivascular PU Films Coated withDifferent Silk Suture Material to Assess Scarring

A rat carotid artery model is described for determining whether asubstance stimulates fibrosis. Wistar rats weighing 300 g to 400 g areanesthetized with halothane. The skin over the neck region is shaved andthe skin is sterilized. A vertical incision is made over the trachea andthe left carotid artery is exposed. A polyurethane film covered withsilk sutures from one of three different manufacturers (3-0 Silk—BlackBraided (Davis & Geck), 3-0 SOFSILK (U.S. Surgical/Davis & Geck), and3-0 Silk-Black Braided (LIGAPAK) (Ethicon, Inc.) is wrapped around adistal segment of the common carotid artery. (The polyurethane film canalso be coated with other agents to induce fibrosis.) The wound isclosed and the animal is allowed to recover.

After 28 days, the rats are sacrificed with carbon dioxide andpressure-perfused at 100 mmHg with 10% buffered formaldehyde. Bothcarotid arteries are harvested and processed for histology. Serialcross-sections are be cut every 2 mm in the treated left carotid arteryand at corresponding levels in the untreated right carotid artery.Sections are stained with H&E and Movat's stains to evaluate tissuegrowth around the carotid artery. Area of perivascular granulationtissue is quantified by computer-assisted morphometric analysis.Thickness of the granulation tissue is the same in the three groupsshowing that tissue proliferation around silk suture is independent ofmanufacturing processes. See FIG. 9.

Example 19 In Vivo Evaluation of Perivascular Silk Powder to AssessScarring

A rat carotid artery model is described for determining whether asubstance stimulates fibrosis. Wistar rats weighing 300 g to 400 g areanesthetized with halothane. The skin over the neck region is shaved andthe skin is sterilized. A vertical incision is made over the trachea andthe left carotid artery is exposed. Silk powder is sprinkled on theexposed artery that is then wrapped with a PU film. Natural silk powderor purified silk powder (without contaminant proteins) is used indifferent groups of animals. Carotids wrapped with PU films only areused as a control group. The wound is closed and the animal is allowedto recover. After 28 days, the rats are sacrificed with carbon dioxideand pressure-perfused at 100 mmHg with 10% buffered formaldehyde. Bothcarotid arteries are harvested and processed for histology. Serialcross-sections can be cut every 2 mm in the treated left carotid arteryand at corresponding levels in the untreated right carotid artery.Sections are stained with H&E and Movat's stains to evaluate tissuegrowth around the carotid artery. Area of tunica intima, tunica mediaand perivascular granulation tissue is quantified by computer-assistedmorphometric analysis.

The natural silk caused a severe cellular inflammation consisting mainlyof a neutrophil and lymphocyte infiltrate in a fibrin network withoutany extracellular matrix or blood vessels. In addition, the treatedarteries were seriously damaged with hypocellular media, fragmentedelastic laminae and thick intimal hyperplasia. Intimal hyperplasiacontained many inflammatory cells and was occlusive in 2/6 cases. Thissevere immune response was likely triggered by antigenic proteinscoating the silk protein in this formulation. On the other end, theregenerated silk powder triggered only a mild foreign body responsesurrounding the treated artery. This tissue response was characterizedby inflammatory cells in extracellular matrix, giant cells and bloodvessels. The treated artery was intact. These results show that removingthe coating proteins from natural silk prevents the immune response andpromotes benign tissue growth. Degradation of the regenerated silkpowder was underway in some histology sections indicating that thetissue response can likely mature and heal over time. See FIG. 10.

Example 20 In Vivo Evaluation of Perivascular Talcum Powder to AssessScarring

A rat carotid artery model is described for determining whether asubstance stimulates fibrosis. Wistar rats weighing 300 g to 400 g areanesthetized with halothane. The skin over the neck region is shaved andthe skin is sterilized. A vertical incision is made over the trachea andthe left carotid artery is exposed. Talcum powder is sprinkled on theexposed artery that is then wrapped with a PU film. Carotids wrappedwith PU films only are used as a control group. The wound is closed andthe animal is recovered. After 1 or 3 months, the rats are sacrificedwith carbon dioxide and pressure-perfused at 100 mmHg with 10% bufferedformaldehyde. Both carotid arteries are harvested and processed forhistology. Serial cross-sections are cut every 2 mm in the treated leftcarotid artery and at corresponding levels in the untreated rightcarotid artery. Sections are stained with H&E and Movat's stains toevaluate tissue growth around the carotid artery. Thickness of tunicaintima, tunica media and perivascular granulation tissue is quantifiedby computer-assisted morphometric analysis. Histopathology results andmorphometric analysis showed the same local response to talcum powder at1 month and 3 months. A large tissue reaction trapped the talcum powderat the site of application around the blood vessel. This tissue wascharacterized by a large number of macrophages within a denseextracellular matrix with few neutrophiles, lymphocytes and bloodvessels. The treated blood vessel appeared intact and unaffected by thetreatment. Overall, this result showed that talcum powder induced a mildlong-lasting fibrotic reaction that was subclinical in nature and didnot harm any adjacent tissue. See FIG. 11.

Example 21 Preparation of Silk Powder

Several pieces of silk braid (Ethicon, 4-0, 638) are cut into lengths ofapprox 0.4 cm. These cut pieces are placed in a 100 ml round bottomflask that contains 50 ml 2M NaOH. The sample is stirred using amagnetic stirrer at room temperature for 24 h. The sample is neutralizedusing concentrated HCl. The neutralized contents are then dialyzedagainst deionized water using cellulose-based dialysis tubing (WMCOapprox 3000; Spectrum). The sample is dialyzed for 48 hours with 5 waterchanges. The dialyzed sample is then poured into a 100 ml round bottomflask. The sample is frozen and freeze-dried to yield a fluffy powderedmaterial.

Example 22 Coating of Medical Implants with a Powdered Silk/PLGA Coating

A medical device (e.g., aneurysm coil) attached to a stainless steel rod(with the aid of a bulldog clip) that is attached to a Fisher overheadstirrer that is orientated vertically. The stirrer is set to rotate at30 rpm. A 2% PLGA (9K, 50:50, Birmingham Polymers) solution (ethylacetate) that contains the powdered silk is sprayed onto the rotatingimplant using an airbrush spray device. The concentration of thepowdered silk in the PLGA solution is altered from 0.1% to 50%. Afterthe spraying process, the device is allowed to air dry for 30 minuteswhile still rotating. The device is then removed from the pipette tipand is further dried under vacuum for 24 h.

Example 23 Coating of Tube with a Powdered Silk/Polyurethane Coating

A polyurethane tube is pushed onto a 1 ml plastic pipette tip. The openend of the pipette tip is attached to a stainless steel rod that isattached to a Fisher overhead stirrer that is orientated horizontally.The stirrer is set to rotate at 30 rpm. A 2% CHRONOFLEX AL 85A (CTBiomaterials) solution (THF) that contains powdered silk (prepared usinga cryomill) is sprayed onto the rotating tube using a TLC spray device.The concentration of the powdered silk in the polyurethane solution isaltered from 0.1% to 50%. After the spraying process, the tube isallowed to air dry for 30 minutes while still rotating. The tube is thenremoved from the pipette tip and is further dried under vacuum for 24 h.

Example 24 Top-Coating of a Coated Tube with a Degradable Coating

The coated tube from Example 24 is reattached to the overhead stirrerand is rotated at 30 rpm. A 10% 20:80 MePEG(750)-PLA block copolymersolution (acetone) is sprayed onto the rotating tube using an TLC spraydevice. After the spraying process, the tube is allowed to air dry for30 minutes while still rotating. The spray coating process can berepeated until the desired thickness or uniformity of coating isobtained. The tube is then removed from the pipette tip and is furtherdried under vacuum for 24 h.

Example 25 Top-Coating of a Coated Tube with a Heparin-ContainingDegradable Coating

The coated tube from Example 24 is reattached to the overhead stirrerand is rotated at 30 rpm. A 10% 20:80 MePEG(750)-PLA block copolymersolution (acetone) that contains various amounts of a heparinbenzalkonium chloride complex (PolySciences) is sprayed onto therotating tube using an TLC spray device. After the spraying process, thetube is allowed to air dry for 30 minutes while still rotating. Thespray coating process can be repeated until the desired thickness oruniformity of coating is obtained. The tube is then removed from thepipette tip and is further dried under vacuum for 24 h.

Example 26 Coating of a Coated Tube with a Heparin Coating

The coated tube from Example 24 is reattached to the overhead stirrerand is rotated at 30 rpm. A solution that contains various amounts of aHeparin benzalkonium chloride complex (PolySciences) in IPA is sprayedonto the rotating tube using a TLC spray device. After the sprayingprocess, the tube is allowed to air dry for 30 minutes while stillrotating. The spray coating process can be repeated until the desiredthickness or uniformity of coating is obtained. The tube is then removedfrom the pipette tip and is further dried under vacuum for 24 h.

Example 27 Coating of Tube with a Powdered Silk/Cyclosporinea/Polyurethane Coating

A polyurethane tube is pushed onto a 1 ml plastic pipette tip. The openend of the pipette tip is attached to a stainless steel rod that isattached to a Fisher overhead stirrer that is orientated horizontally.The stirrer is set to rotate at 30 rpm. A 2% CHRONOFLEX AL 85A solution(THF) that contains the powdered silk and cyclosporine A is sprayed ontothe rotating tube using an TLC spray device. The concentration of thepowdered silk in the polyurethane solution is altered from 0.1% to 50%(w/w relative to the polymer) and the concentration of the CyclosporineA is altered from 0.1% to 10% (w/w relative to the polymer). Afterthespraying process, the tube is allowed to air dry for 30 minutes whilestill rotating. The tube is then removed from the pipette tip and isfurther dried under vacuum for 24 h.

Example 28 Film Impregnated with Silk Fibers

A 20% CHRONOFLEX AL 85A solution (THF) was cast onto a silicone-coatedrelease liner. The solvent allowed to dry. Pieces of 3-0 Silk-BlackBraided (LIGAPAK) (Ethicon, Inc.) were placed on the surface of thepolyurethane film. Drops of THF were then added to the surface of thepolyurethane film. Using a glass scintillation vial as a roller, thesilk strands were embedded into the surface of the polyurethane film.

Example 29 In Situ Forming Silk—Containing Gel

Methylated collagen is prepared by the following process: bovine coriumcollagen is solubilized using pepsin and purified as described in U.S.Pat. No. 4,233,360. This purified, solubilized collagen is precipitatedby neutralization into 0.2 M sodium phosphate, pH 7.2. The precipitateis isolated by centrifugation to a final concentration of 70 mg/ml. Thematerial is dried for two days, and then pulverized. Dry methanolcontaining HCl (to 0.1 N) is added (40 ml) and stirred for four days.Collagen is separated from the acidic methanol, vacuum dried andsterilized by irradiation. The final product is dissolved in water at apH of 3-4.

For delivery as a gel, 10 mg of the methylated collagen, 100 mg of atetra-functional sulfhydryl-PEG (pentaerythritol poly(ethyleneglycol)ether tetra-sulfhydryl), 10,000 MW, and 100 mg of atetra-functional succinimidyl PEG (pentaerythritol poly(ethyleneglycol)ether tetra-succinimidyl glutarate), 10,000 MW, are dissolved inwater at pH 3-4 to a final volume of 1 ml (first component). The secondcomponent is 1 ml of phosphate/carbonate buffer (300 mM sodium monobasicphosphate is mixed with 300 mM sodium carbonate. If required, the pH isadjusted with NaOH or HCl to achieve pH 9.6. The final molarity isapproximately 117 mM phosphate and 183 mM carbonate). Various amounts (1mg to 100 mg) of silk powder (prepared using a cryomill) is added to thephosphate/carbonate buffer. Each component is placed in a syringe andmixed and sprayed on the desired test site using a manual dual-syringedelivery system or a air-assisted dual syringe delivery system(FibriJet, Micromedics).

Example 30 Coating of the Silk Braid with a Polymer/BiologicallyAgent—Direct Dipping

Silk braid (Ethicon, 4-0, 638) is cut into approximately 10 cm lengths.The silk braid is dipped into a chloroform solution ofpoly(lactide-co-glycolide) (PLGA) (9K, 50:50, Birmingham Polymers) andcyclosporine A. The concentration of the PLGA is altered from 0.1% to20% (w/v) and concentration of the cyclosporine A in the solution isaltered from 0.1% to a saturated solution. The silk braid is immersed inthe PLGA/cyclosporine A solution for 5 minutes. The silk braid is thenremoved and air-dried. The cyclosporine A loaded silk braid is thenfurther dried under vacuum. The silk braid is then attached to apolyurethane film by placing the coated-braids on the polyurethane filmand then pressing the film/braids in a heat press for about 10 secondssuch that the coated braid is embedded in the polyurethane film.

Example 31 In Situ Forming Silk—Containing Gel

For delivery as a gel, 200 mg of a tetra-functional succinimidyl PEG(pentaerythritol poly(ethylene glycol)ether tetra-succinimidylglutarate) 10,000 MW s dissolved in water at pH 2.5 (adjusted with HCl)to a final volume of 1 ml (first component). The second component is 1ml of phosphate/carbonate Buffer (300 mM sodium monobasic phosphate ismixed with 300 mM sodium carbonate. If required, the pH is adjusted withNaOH or HCl to achieve pH 9.6. The final molarity is approximately 117mM phosphate and 183 mM carbonate) that contains 200 mg of atetra-functional amino-PEG (pentaerythritol poly(ethyleneglycol)ethertetra-amino), 10,000 MW. Various amounts (1 mg to 200 mg) ofthe silk powder are added to the acidic buffer. Each component is placedin a syringe and is sprayed on the desired test site using a manualdual-syringe delivery system or a air-assisted dual syringe deliverysystem (FibriJet, Micromedics).

Example 32 Cyclosporine A—Containing Coating

A 5% CHRONOFLEX AL 85A solution (chloroform) containing from 0.1% to 10%cyclosporine A is prepared. A piece of polyurethane tubing is immersedin and then withdrawn from the coating solution. The coated sample isair-dried in the fume-hood. Samples of different coating thicknesses areprepared by repeating the dip-coating process. The coated sample is thendried under vacuum for 24 hours.

Example 33 Collagen Synthesis Assay

An in vitro assay is described for determining whether a substancepromotes deposition of extracellular matrix (ECM). Normal human dermalfibroblasts were trypzanized, then re-plated in medium containingascorbic acid-2-phosphate at 150,000 cells per well in a 12-well plate.The cells were cultured at 37° C. and 5% CO₂ for 2-3 weeks with mediachanges every three days so that they formed a 3-D matrix of cells andcollagen. After 14-21 days of culture, the medium was replaced withserum free medium and the cells allowed to rest for 24 hours.

Drug was diluted in DMSO at 10⁻²M, then diluted 10 fold to give a rangeof stock concentrations from 10⁻²M to 10⁻⁸M. Drug was then diluted 1000times in fresh serum free medium and added to the wells in a totalvolume of 3 ml per well. The plate(s) were then incubated for 72 hrs at37° C. After 72 hrs the media was removed from the wells and put intomicrocentrifuge tubes and frozen at −20° C. until assayed.

The amount of collagen synthesized was measured using a Procollagen Type1 C-Peptide (PIP) EIA kit (Takara), where the amount of collagenproduced is stoichiometrically represented by the amount of pro-peptidecleaved from the collagen when it is secreted. Anti-PIP monoclonalantibodies are immobilized on an ELISA plate, the samples added, then asecond PIP monoclonal antibody conjugated to horseradish peroxidase isadded to the wells and incubated. Following incubation, the wells arewashed, a substrate solution is added, and the absorbance measured in aplate reader at 450 nm and compared to a standard curve of PIP (ng/ml).

Example 34 Chick Chorioallantoic Membrane (“CAM”) Assay

This example describes an in vitro assay for determining whether asubstance promotes angiogenesis. Fertilized, domestic chick embryos areincubated for 3 days prior to shell-less culturing. In this procedure,the egg contents are emptied by removing the shell located around theair space. The interior shell membrane is then severed and the oppositeend of the shell is perforated to allow the contents of the egg togently slide out from the blunted end. The egg contents are emptied intoround-bottom sterilized glass bowls and covered with petri dish covers.These are then placed into an incubator at 90% relative humidity and 3%CO₂ and incubated for 3 days. (Alternatively, egg contents can remain inthe shell with the opening covered with parafilm.)

The agent (e.g., paclitaxel) (Sigma) can be mixed at concentrations of0.25, 0.5, 1, 5, 10, 30 μg per 10 ul aliquot of 0.5% aqueousmethylcellulose. Concentrations can be altered depending on the agent.Agents can be mixed with other compatible materials as appropriatedepending on the solubility of the agent. Ten microliter aliquots ofthis solution are dried on parafilm for 1 hour forming disks 2 mm indiameter. The dried disks containing agent are then carefully placed atthe growing edge of each CAM at day 6 of incubation. The day of discplacement can be altered depending on the amount of angiogenesisstimulation by the agent beyond control. Controls are obtained byplacing agent-free methylcellulose disks on the CAMs over the same timecourse. After a 2 day exposure (day 8 of incubation) the vasculature isexamined with the aid of a stereomicroscope. Liposyn II, a white opaquesolution, is injected into the CAM to increase the visibility of thevascular details. The vasculature of unstained, living embryos wereimaged using a Zeiss stereomicroscope which is interfaced with a videocamera (Dage-MTI Inc., Michigan City, Ind.). These video signals arethen displayed at 160× magnification and captured using an imageanalysis system (Vidas, Kontron; Etching, Germany). Image negatives arethen made on a graphics recorder (Model 3000; Matrix Instruments,Orangeburg, N.Y.).

The membranes of the 8 day-old shell-less embryo are flooded with 2%glutaraldehyde in 0.1M sodium cacodylate buffer; additional fixative isinjected under the CAM. After 10 minutes in situ, the CAM is removed andplaced into fresh fixative for 2 hours at room temperature. The tissueis then washed overnight in cacodylate buffer containing 6% sucrose. Theareas of interest are postfixed in 1% osmium tetroxide for 1.5 hours at4° C. The tissues are then dehydrated in a graded series of ethanols,solvent exchanged with propylene oxide, and embedded in Spurr resin.Thin sections are cut with a diamond knife, placed on copper grids,stained, and examined in a Joel 1200EX electron microscope. Similarly,0.5 mm sections are cut and stained with toluene blue for lightmicroscopy.

At day 11 of development, chick embryos are used for the corrosioncasting technique. Mercox resin (Ted Pella, Inc., Redding, Calif.) isinjected into the CAM vasculature using a 30-gauge hypodermic needle.The casting material consists of 2.5 grams of Mercox CL-2B polymer and0.05 grams of catalyst (55% benzoyl peroxide) having a 5 minutepolymerization time. After injection, the plastic is allowed to sit insitu for an hour at room temperature and then overnight in an oven at65° C. The CAM is then placed in 50% aqueous solution of sodiumhydroxide to digest all organic components. The plastic casts are washedextensively in distilled water, air-dried, coated with gold/palladium,and viewed with the Philips 501B scanning electron microscope.

At day 6 of incubation, the embryo is centrally positioned to a radiallyexpanding network of blood vessels; the CAM develops adjacent to theembryo. These growing vessels lie close to the surface and are readilyvisible making this system an idealized model for the study ofangiogenesis. Living, unstained capillary networks of the CAM can beimaged non-invasively with a stereomicroscope.

Transverse sections through the CAM show an outer ectoderm consisting ofa double cell layer, a broader mesodermal layer containing capillarieswhich lie subjacent to the ectoderm, adventitial cells, and an inner,single endodermal cell layer. At the electron microscopic level, thetypical structural details of the CAM capillaries are demonstrated.Typically, these vessels lie in close association with the inner celllayer of ectoderm.

After 48 hours exposure to an agent at concentrations of 0.25, 0.5, 1,5, 10, or 30 μg, each CAM is examined under living conditions with astereomicroscope equipped with a video/computer interface to evaluatethe effects on angiogenesis. This imaging setup is used at amagnification of 160× which permits the direct visualization of bloodcells within the capillaries; thereby blood flow in areas of interestcan be easily assessed and recorded. The change in the amount ofangiogenesis is defined as an area of the CAM (measuring 2-6 mm indiameter) with increased capillary network and vascular blood flow.Throughout the experiments, zones are assessed on a 4 point gradient(Table 1). This scale represents the degree of increase in angiogenesiswith maximal increase represented as a 3 on the vascular gradient scale.Scores of agents are compared with scores of controls. TABLE 1 VASCULARGRADIENT 0  no vascularity 1  some microvascular movement 2* richlyvascularized zone approximately 2 mm in diameter 3* richly vascularizedzone extending beyond the disk (6 mm in diameter)*indicates a positive angiogenesis response

Example 35 Silk Suture Coated with Magnetically Active Particles

The end of a piece of silk 5-0 suture was immersed in a THF solution ofCHRONOFLEX AL 85A polyurethane solution (about 10% w/v). The silk wasremoved, and the coated end was dipped into a vial containingmagnetically active microparticles. The coated silk end was removed, andthe particles were further embedded into the polyurethane coating byrolling the end between two fingertips. The solvent was removed byair-drying.

Example 36 Silk Suture Coated with Magnetically Active Beads

The end of a piece of silk 5-0 suture was immersed in a THF solution ofCHRONOFLEX AL 85A polyurethane solution (about 10% w/v) that containedapproximately 5% w/w (beads to polymer) magnetic beads. The silk wasremoved, and the coated end was dipped into a vial containingmagnetically active microparticies. The coated silk end was removed, andthe particles were further embedded into the polyurethane coating byrolling the end between two fingertips. The solvent was removed byair-drying.

Example 37 In-Vivo Evaluation of Perivascular Pu Films Coated withDegummed or Virgin Silk Strands

Wistar rats weighing 300 g to 400 g are anesthetized with halothane. Theskin over the neck region is shaved and the skin is sterilized. Avertical incision is made over the trachea and the left carotid arteryis exposed. A polyurethane film covered with degummed silk strands,virgin silk strands or a control uncoated PU film is wrapped around adistal segment of the common carotid artery. The wound is closed and theanimal is recovered.

After 28 days, the rats are sacrificed with carbon dioxide andpressure-perfused at 100 mmHg with 10% buffered formaldehyde. Bothcarotid arteries are harvested and processed for histology. Serialcross-sections will be cut every 2 mm in the treated left carotid arteryand at corresponding levels in the untreated right carotid artery.Sections are stained with H&E and Movat's stains to evaluate tissuegrowth around the carotid artery. Thickness of perivascular granulationtissue is quantified by computer-assisted morphometric analysis. Bothtypes of silk markedly increased granulation tissue growth around theblood vessel to the same extent. The silk strands in both groups hasbroken down into small particles (approximately 30 um in diameter)scattered around the blood vessel and surrounded by giant cells,macrophages, proteoglycan matrix and blood vessels. These features aretypical of a foreign body response. The area covered by the foreign bodyresponse was more variable in the virgin silk group than in the degummedsilk group. See FIGS. 12, 13 and 14.

Example 38 Preparation of Silk Powder Using a Cryomill

Fibers of degummed silk were cut into pieces approximately 1-2 cm inlength. The material was then milled to a powder using a cryomill (SpexCertiprep Freezer/Mill—Model 6850). A portion of the milled powder wasthen sieved through a series of different sized metal sieves to obtainsilk powder of different size ranges.

Example 39 Electrospinning of Silk-Loaded Material

20% solutions of PLGA (50:50, Mw^(˜) 54,000) are prepared by dissolving2 g PLGA into 10 mL DCM. Various amounts of silk powder (25-53 um) areadded to each solution such that the silk percentage of the polymersranges from 2% to 50%. Each solution is then loaded into a 10 ml syringefitted with a 18 gauge needle. The syringe is then loaded into a syringepump and 20 kV positive high voltage (by Glassman High Voltage, Inc.) isapplied on the syringe needle. The grounded target drum is a rotatingdrum that has a diameter of about 12 cm. The syringe pump is set to pumpat 25 uL per minute and the drum is rotated at approximately 250 rpm.The distance from the tip of the needle to the outside of the drumsurface is about 14 cm. The rotating drum is moved from side to sideduring the spinning process such that the drum is virtually completelycovered in the spun material. After the spinning process is completed, arazor blade is used to make a cut through the entire length of the spunmaterial. The material is removed from the drum and is further dried ina vacuum oven for 24 hours.

Example 40 MIC (Minimum Inhibitory Concentration) Determination byMicrotitre Broth Dilution Method

A. MIC Assay of Various Gram Negative and Positive Bacteria

MIC assays were conducted essentially as described by Amsterdam, D.1996, “Susceptibility testing of antimicrobials in liquid media,” p.52-111. In Loman, V., ed. Antibiotics in laboratory medicine, 4th ed.Williams and Wilkins, Baltimore, Md. Briefly, a variety of compoundswere tested for antibacterial activity against isolates of P.aeruginosa, K. pneumoniae, E. coli, S. epidermidus and S. aureus in theMIC (minimum inhibitory concentration assay under aerobic conditionsusing 96 well polystyrene microtitre plates (Falcon 1177), and MuellerHinton broth at 37° C. incubated for 24 h. (MHB was used for mosttesting except C721 (S. pyogenes), which used Todd Hewitt broth, andHaemophilus influenzae, which used Haemophilus test medium (HTM)) Testswere conducted in triplicate. The results are provided below in Table 2.TABLE 2 MINIMUM INHIBITORY CONCENTRATIONS OF THERAPEUTIC AGENTS AGAINSTVARIOUS GRAM NEGATIVE AND POSITIVE BACTERIA Bacterial Strain P.aeruginosa K. pneumoniae E. coli S. aureus PAE/K799 ATCC13883 UB1005ATCC25923 S. epidermidis S. pyogenes H187 C238 C498 C622 C621 C721 Wt wtwt wt wt wt Drug Gram − Gram − Gram − Gram + Gram + Gram + doxorubicin10⁻⁵ 10⁻⁶ 10⁻⁴ 10⁻⁵ 10⁻⁶ 10⁻⁷ mitoxantrone 10⁻⁵ 10⁻⁶ 10⁻⁵ 10⁻⁵ 10⁻⁵ 10⁻⁶5-fluorouracil 10⁻⁵ 10⁻⁶ 10⁻⁶ 10⁻⁷ 10⁻⁷ 10⁻⁴ methotrexate N 10⁻⁶ N 10⁻⁵N 10⁻⁶ etoposide N 10⁻⁵ N 10⁻⁵ 10⁻⁶ 10⁻⁵ camptothecin N N N N 10⁻⁴ Nhydroxyurea 10⁻⁴ N N N N 10⁻⁴ cisplatin 10⁻⁴ N N N N N tubercidin N N NN N N 2- N N N N N N mercaptopurine 6- N N N N N N mercaptopurineCytarabine N N N N N NActivities are in Molar concentrationsWt = wild typeN = No activityB. MIC of Antibiotic-Resistant Bacteria

Various concentrations of the following compounds, mitoxantrone,cisplatin, tubercidin, methotrexate, 5-fluorouracil, etoposide,2-mercaptopurine, doxorubicin, 6-mercaptopurine, camptothecin,hydroxyurea and cytarabine were tested for antibacterial activityagainst clinical isolates of a methicillin resistant S. aureus and avancomycin resistant pediocoocus clinical isolate in an MIC assay asdescribed above. Compounds which showed inhibition of growth (MIC valueof <1.0×10-3) included: mitoxantrone (both strains), methotrexate(vancomycin resistant pediococcus), 5-fluorouracil (both strains),etoposide (both strains), and 2-mercaptopurine (vancomycin resistantpediococcus).

Example 41 Coating of a Hip Implant with Silk/PLGA

A solution of 5 g PLGA (50:50, IV=0.15, Birmingham Polymers, Inc.) isdissolved in 100 mL dichloromethane. 1 g of powdered silk (25-53 um,prepared using the cryomill as sieving as described above) is mixed intothe solution. The hip implant (SECUR-FIT HA, Stryker Orthopaedics) isplaced in a clamp system such that the ball segment of the hip implantis secured in the clamp. The clamp is then secured to an overheadstirrer (Fisher Scientific). The stirrer is set to a speed of about 30rpm. The silk/PLGA solution is placed in a glass TLC spray device(Sigma-Aldrich Corp). Approx. ⅓ of the implant below the polishedsection of the implant is coated with the silk/PLGA using the TLC spraydevice (connected to a nitrogen tank). The spray device is swirledduring the spraying process to ensure that the silk is evenly dispersedin the PLGA solution. The rate of spray application is controlled suchthat the solution does not drip off the device. Once an initial coatingis accomplished, the spraying process is stopped and the device is airdried. If required the spray coating/drying process can be repeateduntil the desired thickness is accomplished. After the final air dryingstep, the device is removed from the clamp and is placed in a vacuumoven. The implant is dried for 6 hours under vacuum. Other examples offibrosing agents that may be similarly coated onto a hip implant deviceinclude: fibronectin, talc, silica, starch, poly(ethyl cyanoacrylate),polylysine, bleomycin, and CTGF. Other implant devices such as a kneeimplant, shoulder implant and a digit implant can be coated in a mannersimilar to that described above.

Example 42 Coating of a Hip Implant with Silk/Cyclosporine A/PLGA

A solution of 5 g PLGA (50:50, IV=0.15, Birmingham Polymers, Inc.) isdissolved in 100 mL chloroform. 1 g of powdered silk (25-53 um, preparedusing the cryomill as sieving as described above) is mixed into thesolution. 0.5 mg cyclosporine A is added to the solution. The hipimplant (SECUR-FIT HA, Stryker Orthopaedics) is placed in a clamp systemsuch that the ball segment of the hip implant is secured in the clamp.The clamp is then secured to an overhead stirrer (Fisher Scientific).The stirrer is set to a speed of about 30 rpm. The silk/PLGA solution isplaced in a glass TLC spray device (Sigma-Aldrich Corp). Approx. ⅓ ofthe implant below the polished section of the implant is coated with thesilk/PLGA using the TLC spray device (connected to a nitrogen tank). Thespray device is swirled during the spraying process to ensure that thesilk is evenly dispersed in the PLGA solution. The rate of sprayapplication is controlled such that the solution does not drip off thedevice. Once an initial coating is accomplished, the spraying process isstopped and the device is air dried. If required the spraycoating/drying process can be repeated until the desired thickness isaccomplished. After the final air drying step, the device is removedfrom the clamp and is placed in a vacuum oven. The implant is dried for6 hours under vacuum. Other examples of fibrosing agents that may besimilarly coated onto a hip implant device include: talc, silica,starch, fibronectin, poly(ethyl cyanoacrylate), polylysine, bleomycin,and CTGF. Other implant devices such as a knee implant, shoulder implantand a digit implant can be coated in a manner similar to that describedabove.

Example 43 Coating of a Hip Implant with Silk

A silk solution is prepared by adding 10 g virgin silk fibers to 100 mLhexafluoroisopropanol (HFIP). The solution is allowed to stir for 48hours at room temperature. The hip implant (SECUR-FIT HA, StrykerOrthopaedics) is placed in a clamp system such that the ball segment ofthe hip implant is secured in the clamp. The clamp is then secured to anoverhead stirrer (Fisher Scientific). The stirrer is set to a speed ofabout 30 rpm. A Pasteur pipette is used to drip the silk/HFIP solutiononto the hydroxyapatite (HA) coated portion of the hip implant. Thevolume added with each drop is such that the solution does not drip fromthe implant. Once the HA coating is wetted with the silk/HFIP solution,the material application is stopped and the implant is allowed to airdry. The process is repeated again and after the drying step, the deviceis removed from the clamp and is placed in a vacuum oven. The implant isdried for 6 hours under vacuum. Other examples of fibrosing agents thatmay be similarly coated onto a hip implant device include: talc, silica,starch, fibronectin, poly(ethyl cyanoacrylate), polylysine, bleomycin,and CTGF. Other implant devices such as a knee implant, shoulder implantand a digit implant can be coated in a manner similar to that describedabove.

Example 44 Coating of an Endosteal Implant with Silk/Plga

A solution of 5 g PLGA (50:50, IV=0.15, Birmingham Polymers, Inc.) isdissolved in 100 mL dichloromethane. 1 g of powdered silk (25-53 um,prepared using the cryomill as sieving as described above) is mixed intothe solution. The endosteal implant is placed in a clamp system suchthat the threaded section is readily accessible. The clamp is thensecured to an overhead stirrer (Fisher Scientific). The stirrer is setto a speed of about 30 rpm. The silk/PLGA solution is placed in a glassTLC spray device (Sigma-Aldrich Corp). The threaded section of theimplant is coated with the silk/PLGA using the TLC spray device(connected to a nitrogen tank). The spray device is swirled during thespraying process to ensure that the silk is evenly dispersed in the PLGAsolution. The rate of spray application is controlled such that thesolution does not drip off the device. Once an initial coating isaccomplished, the spraying process is stopped and the device is airdried. If required the spray coating/drying process can be repeateduntil the desired thickness is accomplished. After the final air dryingstep, the device is removed from the clamp and is placed in a vacuumoven. The implant is dried for 6 hours under vacuum. Other examples offibrosing agents that may be similarly coated onto the implant deviceinclude: talc, silica, starch, fibronectin, poly(ethyl cyanoacrylate),polylysine, bleomycin, and CTGF.

Example 45 Coating of an Endosteal Implant with Silk/PLGA

A solution of 10 g PLGA (50:50, IV=0.15, Birmingham Polymers, Inc.) isdissolved in 100 mL dichloromethane. The threaded portion of theendosteal implant is dipped into the PLGA solution. The coated device ispartially dried and then the silk powder is sprinkled onto the coatedsection of the coated implant. The implant is then rolled on a TEFLONsheet such that the silk particles are embedded into the PLGA coating.The implant is then air dried for 3 hours. After the air drying step,the device is placed in a vacuum oven. The implant is dried for 6 hoursunder vacuum. Other examples of fibrosing agents that may be similarlycoated onto the implant device include: talc, silica, starch,fibronectin, poly(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Example 46 Coating of an Intramedullary Pin with Silk/PLGA

A solution of 10 g PLGA (50:50, IV=0.25, Birmingham Polymers, Inc.) isdissolved in 100 mL dichloromethane. The lower half of a intramedullarypin (cat #: 167430000, Sanatmetal) implant is dipped into the PLGAsolution. The coated device is partially dried and then the silk powderis sprinkled onto the coated section of the coated implant. The implantis then rolled on a Teflon sheet such that the silk particles areembedded into the PLGA coating. The implant is then air dried for 3hours. After the air drying step, the device is placed in a vacuum oven.The implant is dried for 6 hours under vacuum. Other examples offibrosing agents that may be similarly coated onto the implant deviceinclude: talc, silica, starch, fibronectin, poly(ethyl cyanoacrylate),polylysine, bleomycin, and CTGF.

Example 47 Coating of an Intramedullary Pin with Silk/POLYURETHANE

A solution of 10 g CHRONOFLEX AL 85A (CT Biomaterials) is dissolved in100 mL THF. The lower half of a intramedullary pin (cat #: 167430000,Sanatmetal) implant is dipped into the polyurethane solution. The coateddevice is partially dried and then the silk powder is sprinkled onto thecoated section of the coated implant. The implant is then rolled on aTEFLON sheet such that the silk particles are embedded into thepolyurethane coating. The implant is then air dried for 3 hours. Afterthe air drying step, the device is placed in a vacuum oven. The implantis dried for 6 hours under vacuum. Other examples of fibrosing agentsthat may be similarly coated onto the implant device include: talc,silica, starch, fibronectin, poly(ethyl cyanoacrylate), polylysine,bleomycin, and CTGF.

Example 48 Coating of an Intramedullary Pin with Silk/PLGA

A solution of 10 g PLGA (50:50, IV=0.25, Birmingham Polymers, Inc.) isdissolved in 100 mL dichloromethane. A stainless steel wire is loopedthrough the top hole of a broad bone plate (cat #: 934016005,Sanatmetal). The implant is dipped into the PLGA solution. The coateddevice is partially dried and then the silk powder is sprinkled onto thecoated section of the coated implant. The implant is then air dried for3 hours. After the air drying step, the device is placed in a vacuumoven. The implant is dried for 6 hours under vacuum. Other examples offibrosing agents that may be similarly coated onto the implant deviceinclude: talc, silica, starch, fibronectin, poly(ethyl cyanoacrylate),polylysine, bleomycin, and CTGF.

Example 49 Coating of a Gastric Restriction Device withTALC/Polyurethane

A solution of 10 g CHRONOFLEX AL 85A (CT Biomaterials) is dissolved in100 mL THF. The outer surface of the ring portion of a BIOENTERICSLAP-BAND System (Inamed Health) is dipped into the polyurethanesolution. The coating is air dried until it is tacky at which point talc(hydrous magnesium silicate, powder particle size 10 μm, Aldrich Corp.)is sprinkled over the tacky coating. The device is gently shaken toremove the excess material. A TEFLON rod is then gently rolled over thesurface to further embed the talc into the coating. The implant is thenair dried for 2 hours. After the air drying step, the device is placedin a vacuum oven. The implant is dried for 24 hours under vacuum. Otherexamples of fibrosing agents that may be similarly coated onto theimplant device include: silica, fibronectin, starch, silk, poly(ethylcyanoacrylate), polylysine, bleomycin, and CTGF.

Example 50 Coating of a Gastric Restriction Device with Silk/PLGA

A solution of 10 g PLGA (50:50, IV=0.25, Birmingham Polymers, Inc.) isdissolved in 100 mL ethyl acetate. The outer surface of the ring portionof the BioEnterics LAP-BAND System (Inamed Health) is dipped into thepolyurethane solution. The coating is air dried until it is tacky atwhich point silk powder (25-53 um, Prepared using a cryomill and sieves)is sprinkled over the tacky coating. The device is gently shaken toremove the excess material. A TEFLON rod is then gently rolled over thesurface to further embed the silk into the coating. The implant is thenair dried for 2 hours. After the air drying step, the device is placedin a vacuum oven. The implant is dried for 24 hours under vacuum. Otherexamples of fibrosing agents that may be similarly coated onto theimplant device include: talc, silica, fibronectin, starch, poly(ethylcyanoacrylate), polylysine, bleomycin, and CTGF.

Example 51 Coating of a Soft Palate Implant Device with Silk/PLGA

A solution of 2 g PLGA (50:50, IV=0.15, Birmingham Polymers, Inc.) isdissolved in 100 mL ethyl acetate. The end of a PILLAR palatal implant(Restore Medical, Inc) is held using clamp. The clamp is then secured toan overhead stirrer (Fisher Scientific). The stirrer is set to a speedof about 30 rpm. The PLGA solution is placed in a glass TLC spray device(Sigma-Aldrich Corp) and the device is sprayed with the PLGA solutionuntil a thin coating of PLGA covered the device. The coating is airdried until it is tacky. Using a pair of tweezers, the device is removedfrom the clamp and silk powder (25-53 um, prepared using a cryomill andsieves) is sprinkled over the tacky coating. The device is gently shakento remove the excess material. The implant is then air dried for 2hours. After the air drying step, the device is placed in a vacuum oven.The implant is dried for 24 hours under vacuum. Other examples offibrosing agents that may be similarly coated onto the implant deviceinclude: talc, silica, starch, poly(ethyl cyanoacrylate), polylysine,bleomycin, and CTGF.

Example 52 Coating of a Surgical Mesh with Talc/Polyurethane

A solution of 10 g CHRONOFLEX AL 85A (CT Biomaterials) is dissolved in100 mL THF. 1 g talc (hydrous magnesium silicate, powder particle size10 μm, Aldrich Corp.) is then added to the solution. A PROCEED SurgicalMesh (Ethicon) layed flat onto a piece of silicone coated release liner.The silk/PLGA solution is placed in a glass TLC spray device(Sigma-Aldrich Corp). The surface of the mesh is then coated with thepolyurethane/talc solution using the TLC spray device (connected to anitrogen tank). The spray device is swirled during the spraying processto ensure that the talc is evenly dispersed in the polyurethanesolution. The rate of spray application is controlled such that thesolution does not drip off the device. Once an initial coating isaccomplished, the spraying process is stopped and the device is airdried. If required the spray coating/drying process can be repeateduntil the desired thickness is accomplished. After the final air dryingstep, the device is removed from the clamp and is placed in a vacuumoven. The implant is dried for 6 hours under vacuum. Other examples offibrosing agents that may be similarly coated onto a hip implant deviceinclude: talc, silica, starch, silk, poly(ethyl cyanoacrylate),polylysine, bleomycin, and CTGF.

Example 53 Coating of a Surgical Mesh with Silk/PLGA

A solution of 2 g PLGA (50:50, IV=0.15, Birmingham Polymers, Inc.) isdissolved in 100 mL ethyl acetate. 1 g of powdered silk (25-53 um,prepared using the cryomill as sieving as described above) is mixed intothe solution. A Bard Mesh (Flat Sheets, Cat # 0112680 3″×6″ (7.5 cm×15cm), DAVOL) laid flat onto a piece of silicone coated release liner. Thesilk/PLGA solution is placed in a glass TLC spray device (Sigma-AldrichCorp). The surface of the mesh is then coated with the PLGA/silksolution using the TLC spray device (connected to a nitrogen tank). Thespray device is swirled during the spraying process to ensure that thesilk is evenly dispersed in the PLGA solution. Once an initial coatingis accomplished, the spraying process is stopped and the device is airdried. If required the spray coating/drying process can be repeated.After the final air drying step, the mesh is placed in a vacuum oven andis dried for 6 hours under vacuum. Other examples of fibrosing agentsthat may be similarly coated onto the mesh include: talc, fibronectin,silica, starch, poly(ethyl cyanoacrylate), polylysine, bleomycin, andCTGF.

Example 54 Incorporation of Silk into a Surgical Mesh

A Bard Hernia Mesh (Flat Sheets, Cat # 0112680 3″×6″ (7.5 cm×15 cm),DAVOL) is laid flat in a sheet of glass. Several silk sutures(PERMA-HAND Silk Suture—Taper Point, Cat: 7730G, Ethicon) are then sewnonto the mesh by inserting the needle through the mesh from one side ifthe mesh to the other side of the mesh. The silk is traversed throughthe mesh at least 4 times for each suture. The excess suture material isthe cut away.

Example 55 Incorporating Silk onto an Embolization Coil

A 2 ply silk thread is looped around the platinum wire of a detachableTORNADO embolization coil (Cook, Inc) and then a knot is tied to securethe silk to the platinum coil. This process is repeated several timesuntil the amount of silk present accounts for about 5% of the fiberspresent.

Example 56 Coating of a Septal Occlusion Device with Silk

A 5% silk solution in HFIP is prepared by adding 1 g virgin silk yard to20 mL HFIP. The solution is stirred for 48 hours. The resultant solutionis then dripped onto the PTFE portion of a HELEX septal occluder device(W. L. Gore). Once most of the PTFE protion of the device had been incontact with the HFIP/Silk solution, the device is air dried and is thenvacuum dried for 24 hours.

Example 57 Coating of a Septal Occlusion Device with Polylysine

A 2% solution of poly(Lysine) [poly-D-lysine hydrobromide, mol wt150,000-300,000 Sigma-Aldrich] is prepared by dissolving 0.1 g in 2 mLdeionized water. The solution is poured into a small metal tray. AnAMPLATZER septal occluder (AGA Medical Corporation, USA) is then dippedinto the solution and is covered in the solution by using a Pasteurpipetted squirt the solution over the device. The device is then removedfrom the tray and is placed on a TEFLON sheet and is allowed to air dry.The device is then dried under vacuum for 24 hours.

Example 58 Coating of a Fallopian Tube Implant with Silk/PLGA

A solution of 2 g PLGA (50:50, IV=0.15, Birmingham Polymers, Inc.) isdissolved in 100 mL ethyl acetate. 1 g of powdered silk (25-53 um,prepared using the cryomill as sieving as described above) is mixed intothe solution. The “stent” portion of the ECLIPSE permanent contraceptivedevice (Ovion, Redwood City, Calif.) is clamped using a pair of tweezersand a wire strand. The tweezers are then secured to an overhead stirrer(Fisher Scientific). The stirrer is set to a speed of about 45 rpm. Thesilk/PLGA solution is placed in a glass TLC spray device (Sigma-AldrichCorp). Approximately 1/3 of the implant below the polished section ofthe implant is coated with the silk/PLGA using the TLC spray device(connected to a nitrogen tank). The spray device is swirled during thespraying process to ensure that the silk is evenly dispersed in the PLGAsolution. The rate of spray application is controlled such that thesolution does not drip off the device. Once an initial coating isaccomplished, the spraying process is stopped and the device is airdried. If required the spray coating/drying process can be repeateduntil the desired thickness is accomplished. After the final air dryingstep, the device is removed from the clamp and is placed in a vacuumoven. The implant is dried for 6 hours under vacuum. Other examples offibrosing agents that may be similarly coated onto a device include:talc, silica, starch, fibronectin, poly(ethyl cyanoacrylate),polylysine, bleomycin, and CTGF.

Example 59 Coating of a Vas Deferens Clip with Silk/PLGA

A solution of 2 g PLGA (50:50, IV=0.15, Birmingham Polymers, Inc.) isdissolved in 100 mL ethyl acetate. A vas deferens clip (VASCLIP, VMBC,LLC, Roseville, Minn.) is dipped into the PLGA solution and is air drieduntil it is tacky. The clip is then added to powdered silk (25-53 um,prepared using the cryomill as sieving) that is in a beaker. The clip isshaken in the beaker with the powdered silk. The clip is removed fromthe beaker of silk and gently shaken to remove excess silk. A TELFON rodis rolled over the surface of the coated clip to embed the silk powderfurther into the coating. The clip is then air dried for 6 hours afterwhich it is vacuum dried for 24 hours.

Other examples of fibrosing agents that may be similarly coated onto adevice include: talc, silica, starch, fibronectin, poly(ethylcyanoacrylate), polylysine, bleomycin, and CTGF.

Example 60 Incorporation of Silk into a Bulking Agent

50 mg powdered silk (25-53 um, prepared using the cryomill as sieving)is added to 2.5 mL of a glutaradehyde crosslinked bovine collagenssolution (35 mg/mL) [CONTIGEN, CR Bard]. The solution is vortexed toproduce the final suspension. Other examples of fibrosing agents thatmay be similarly coated onto a device include: talc, silica,fibronectin, starch, poly(ethyl cyanoacrylate), polylysine, bleomycin,and CTGF.

Example 61 Coating of Silk onto a Prosthetic Anal Sphincter Device

A solution of 10 g CHRONOFLEX AL 85A (CT Biomaterials) is dissolved in100 mL THF. The cuff portion of an ACTICON NEOSPHINCTER is placed on aTELFON sheet. The silk/polyurethane solution is placed in a glass TLCspray device (Sigma-Aldrich Corp). The cuff portion of the implant iscoated with a thin coating of the silk/polyurethane using the TLC spraydevice (connected to a nitrogen tank). Once an initial coating isaccomplished, the spraying process is stopped and the device is airdried to produce a tacky coating. Powdered silk (25-53 um, preparedusing the cryomill as sieving) is then sprinkled over the tacky coating.A TELFON rod is then rolled over the surface of the device to aid in theembedding of the silk into the coating. The excess silk powder is thenshaken off the device. The device is air dried for 24 hours after whichit is dried under vacuum for 24 hours. Other examples of fibrosingagents that may be similarly coated onto a device include: talc, silica,fibronectin, starch, poly(ethyl cyanoacrylate), polylysine, bleomycin,and CTGF.

Example 62 Incorporation of Silk onto an External Fixation Device

A solution of 10 g PLGA (50:50, IV=0.15, Birmingham Polymers, Inc.) isdissolved in 100 mL dichloromethane. 1 g of powdered silk (25-53 um,prepared using the cryomill as sieving as described above) is mixed intothe solution. The through skin components (The HOFFMANN II HYBRIDEXTERNAL FIXATION System, Stryker) that screw into the bone are dippedinto the PLGA/Silk solution. The lower ⅕ of these pins are coated. Thecoated pins are air dried and then vacuum dried.

Example 63 Incorporation of Silk into Surgical Film Implant

A 10% solution of a 70:30 PLLA:PDLLA polymer (RESOMER LR 708, BoehringerIngelheim, KG, Germany) is prepared by dissolving 1 g of the polymer in10 mL DCM. 1 g powdered silk (25-53 um, prepared using the cryomill andsieving) is added to the solution. The solution is stirred for 1 hour.The solution is cast into a film on a release liner using a 40 milcasting knife. The film is dried in forced-air oven (50° C., 3 hours)and then in a vacuum oven for 24 hours.

Example 64 Dripped-on Cyclosporine a Samples

A polyurethane (PU) (CHRONOFLEX AL 85A) is dissolved in tetrahydrofuran(THF) to form a 20% solution (20 mL). The PU film is prepared by castingthe PU solution on release liner (using 40MIL opening knife). The filmis dried in forced-air oven (50° C.) and then in a vacuum oven. Thefinal film thickness is about 100-120 μm). Cyclosporin-A is dissolved inethanol (500 ug/mL) to form a cyclosporin-A ethanol solution. A 50 μlaliquot of cyclosporin-A solution is dripped onto the 8×8 mm2 (precut)PU film. The ethanol is evaporated in fume hood and the PU samples arefurther dried in vacuum oven.

Example 65 Encapsulated Cyclosporine A Samples

A 20% polyurethane (CHRONOFLEX AL 85A) solution in THF (2 g PU in 10 mLTHF, 20 mL glass scintillation vial) is prepared. 230 uL of a 100 ug/mLcyclosporine A/chloroform solution is added to the PU solution. Thesolution is stirred using a magnetic stirrer for 2 hours. ThePU/cyclosporine A solution is cast into a film on a release liner usinga 40 mil casting knife. The film is dried in forced-air oven (50° C.)and then in a vacuum oven. The final film thickness is about 100-120μm).

Example 66 Release Study and Total Concent Analysis for Cyclosporin fromPolyurethane Film

The release of cyclosporine A from a polyurethane film is analyzed byHPLC using the following parameters. Mobile Phase 35:65:5:0.1(water/acetonitrile, tert-butylmethylether, phosphoric acid) Wavelength210 nm Column ACE C18 150 × 4.6 mm 5 μm Flow rate 1.2 mL/min Diluent for1:1 (acetonitrile/water) samples

Standards are prepared as follows: Approximately 25 mg of cyclosporineis weighted into a 25 mL volumetric flask. A diluent (1:1acetonitrile/water) is added to dissolve the cyclosporine and diluent isadded to achieve the correct volume. The following dilustions (shown inthe table below) are made to obtain standards of 0.2, 0.5, 2, 5, 10 and20 μg/mL. Stock solution Dilution Final volume Final concentrationconcentration (μg/mL) volume (mL) (mL) (μg/mL) 1000 8 10 800 1000 5 10500 1000 3 10 300 1000 2 10 200 1000 1 10 100 100 1 10 10 500 1 10 50 501 10 0.5 800 1 10 80 80 1 10 0.8 200 1 10 20 20 1 10 2Release Studies:

Release studies are performed as follows. A PU film is cut into 1 cm×1cm piece, if not already this size, and weighed accurately into a 15 cmtest tube. 14 mL of release media are dispensed into each test tubecontaining the sample, capped, and placed on a rotator at 37° C. untilnext time point. The time points are 5 hours, 1 day, 2 days, 3 days, 4days, 5 days and then every other day after the first week until drug isnot detected or until otherwise decided. At each time point, the sampleis transferred into a new test tube and 14 mL of release media areadded. The sample is placed back into the 37° C. oven until the nexttime point. The release media solution is injected at various timepoints directly onto the HPLC column for analysis.

Total Content Analysis:

A PU film is cut into 1 cm×1 cm piece, if not already this size, andweigh accurately into a 15 cm test tube. 0.5 mL of choloform is added toeach test tube and completely dissolve the sample. Once the sample isdissolved, 6.0 mL of acetonitrile is added to each sample. The sample iscapped and shaken vigorously to precipitate the polyurethane. The sampleis centrifuged at 2500 rpm for 10 minutes. 5.0 mL of the supernatant istransferred into a clean test tube and dried under nitrogen at 35° C.The dried samples are reconstituted in 1.0 mL of acetonitrile andinjected into the HPLC. The results of the release study forpolyurethane films loaded with 1.25% and 0.125% cyclosporine are shownin FIG. 15.

From the foregoing, it is appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

All of the above U.S. patents, U.S. patent application publications,U.S. patent applications, foreign patents, foreign patent applicationsand non-patent publications referred to in this specification and/orlisted in the Application Data Sheet are incorporated herein byreference, in their entirety.

1-729. (canceled)
 730. A method comprising introducing into a patient inneed thereof, a therapeutically effective amount of a fibrosing agent ora composition comprising a fibrosing agent, where the fibrosing agentinduces a fibrotic response at a specific site within the patient,thereby providing the patient with treatment or prevention of ananeurysm.
 731. (canceled)
 732. The method of claim 730 wherein the agentpromotes angiogenesis.
 733. The method of claim 730 wherein the agentpromotes fibroblast migration.
 734. The method of claim 730 wherein theagent promotes fibroblast proliferation.
 735. The method of claim 730wherein the agent promotes deposition of extracellular matrix (ECM).736. The method of claim 730 wherein the agent promotes tissueremodeling.
 737. The method of claim 730 wherein the agent is anarterial vessel wall irritant.
 738. The method of claim 730 wherein thefibrosing agent is or comprises silk. 739-743. (canceled)
 744. Themethod of claim 730 wherein the fibrosing agent is or comprisesbleomycin. 745-767. (canceled)
 768. The method of claim 730, wherein thecomposition further comprises a second pharmaceutically active agent.769. (canceled)
 770. The method of claim 730, wherein the compositionfurther comprises an agent that inhibits infection. 771-847. (canceled)848. A method comprising introducing into a patient in need thereof, atherapeutically effective amount of a fibrosing agent or a compositioncomprising a fibrosing agent, where the fibrosing agent induces afibrotic response at a specific site within the patient, therebyproviding the patient with embolization.
 849. (canceled)
 850. The methodof claim 848 wherein the agent promotes angiogenesis.
 851. The method ofclaim 848 wherein the agent promotes fibroblast migration.
 852. Themethod of claim 848 wherein the agent promotes fibroblast proliferation.853. The method of claim 848 wherein the agent promotes deposition ofextracellular matrix (ECM).
 854. The method of claim 848 wherein theagent promotes tissue remodeling.
 855. The method of claim 848 whereinthe agent is an arterial vessel wall irritant.
 856. The method of claim848 wherein the fibrosing agent is or comprises silk. 857-861.(canceled)
 862. The method of claim 848 wherein the fibrosing agent isor comprises bleomycin. 863-885. (canceled)
 886. The method of claim848, wherein the composition further comprises a second pharmaceuticallyactive agent.
 887. (canceled)
 888. The method of claim 848, wherein thecomposition further comprises an agent that inhibits infection.889-6268. (canceled)
 6269. A medical device comprising a vascular coilimplant and a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.
 6270. (canceled)
 6271. The device of claim 6269 whereinthe fibrosing agent promotes angiogenesis.
 6272. The device of claim6269 wherein the fibrosing agent promotes fibroblast migration. 6273.The device of claim 6269 wherein the fibrosing agent promotes fibroblastproliferation.
 6274. The device of claim 6269 wherein the fibrosingagent promotes deposition of extracellular matrix (ECM).
 6275. Thedevice of claim 6269 wherein the fibrosing agent promotes tissueremodeling.
 6276. The device of claim 6269 wherein the fibrosing agentis an arterial vessel wall irritant.
 6277. (canceled)
 6278. (canceled)6279. The device of claim 6269 wherein the fibrosing agent is orcomprises silk. 6280-6283. (canceled)
 6284. The device of claim 6269wherein the fibrosing agent is or comprises bleomycin. 6285-6340.(canceled)
 6341. The device of claim 6269, further comprising a secondpharmaceutically active agent.
 6342. (canceled)
 6343. The device ofclaim 6269, further comprising an agent that inhibits infection.6344-6396. (canceled)
 6397. A medical device comprising a vaso-occlusivecoil implant and a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.
 6398. (canceled)
 6399. The device of claim 6397 whereinthe fibrosing agent promotes angiogenesis.
 6400. The device of claim6397 wherein the fibrosing agent promotes fibroblast migration. 6401.The device of claim 6397 wherein the fibrosing agent promotes fibroblastproliferation.
 6402. The device of claim 6397 wherein the fibrosingagent promotes deposition of extracellular matrix (ECM).
 6403. Thedevice of claim 6397 wherein the fibrosing agent promotes tissueremodeling.
 6404. The device of claim 6397 wherein the fibrosing agentis an arterial vessel wall irritant.
 6405. (canceled)
 6406. (canceled)6407. The device of claim 6397 wherein the fibrosing agent is orcomprises silk. 6408-6411. (canceled)
 6412. The device of claim 6397wherein the fibrosing agent is or comprises bleomycin. 6413-6468.(canceled)
 6469. The device of claim 6397, further comprising a secondpharmaceutically active agent.
 6470. (canceled)
 6471. The device ofclaim 6397, further comprising an agent that inhibits infection.6472-6520. (canceled)
 6521. A medical device comprising a vaso-occlusionimplant and a fibrosing agent, where the fibrosing agent induces afibrotic response between the device and a patient in which the deviceis implanted.
 6522. (canceled)
 6523. The device of claim 6521 whereinthe fibrosing agent promotes angiogenesis.
 6524. The device of claim6521 wherein the fibrosing agent promotes fibroblast migration. 6525.The device of claim 6521 wherein the fibrosing agent promotes fibroblastproliferation.
 6526. The device of claim 6521 wherein the fibrosingagent promotes deposition of extracellular matrix (ECM).
 6527. Thedevice of claim 6521 wherein the fibrosing agent promotes tissueremodeling.
 6528. The device of claim 6521 wherein the fibrosing agentis an arterial vessel wall irritant.
 6529. (canceled)
 6530. (canceled)6531. The device of claim 6521 wherein the fibrosing agent is orcomprises silk. 6532-6535. (canceled)
 6536. The device of claim 6521wherein the fibrosing agent is or comprises bleomycin. 6537-6592.(canceled)
 6593. The device of claim 6521, further comprising a secondpharmaceutically active agent.
 6594. (canceled)
 6595. The device ofclaim 6521, further comprising an agent that inhibits infection.6596-6644. (canceled)
 6645. A medical device comprising a non-coiledvaso-occlusive implant and a fibrosing agent, where the fibrosing agentinduces a fibrotic response between the device and a patient in whichthe device is implanted.
 6646. (canceled)
 6647. The device of claim 6645wherein the fibrosing agent promotes angiogenesis.
 6648. The device ofclaim 6645 wherein the fibrosing agent promotes fibroblast migration.6649. The device of claim 6645 wherein the fibrosing agent promotesfibroblast proliferation.
 6650. The device of claim 6645 wherein thefibrosing agent promotes deposition of extracellular matrix (ECM). 6651.The device of claim 6645 wherein the fibrosing agent promotes tissueremodeling.
 6652. The device of claim 6645 wherein the fibrosing agentis an arterial vessel wall irritant.
 6653. (canceled)
 6654. (canceled)6655. The device of claim 6645 wherein the fibrosing agent is orcomprises silk. 6656-6659. (canceled)
 6660. The device of claim 6645wherein the fibrosing agent is or comprises bleomycin. 6661-6716.(canceled)
 6717. The device of claim 6645, further comprising a secondpharmaceutically active agent.
 6718. (canceled)
 6719. The device ofclaim 6645, further comprising an agent that inhibits infection.6720-9244. (canceled)
 9245. A method of making a medical devicecomprising combining i) a vaso-occlusive coil implant, with ii) afibrosing agent or a composition comprising a fibrosing agent, where thefibrosing agent induces a fibrotic response between the device and apatient in which the device is implanted.
 9246. (canceled)
 9247. Themethod of claim 9245 wherein the fibrosing agent promotes angiogenesis.9248. The method of claim 9245 wherein the fibrosing agent promotesfibroblast migration.
 9249. The method of claim 9245 wherein thefibrosing agent promotes fibroblast proliferation.
 9250. The method ofclaim 9245 wherein the fibrosing agent promotes deposition ofextracellular matrix (ECM).
 9251. The method of claim 9245 wherein thefibrosing agent promotes tissue remodeling.
 9252. The method of claim9245 wherein the fibrosing agent is an arterial vessel wall irritant.9253. (canceled)
 9254. (canceled)
 9255. The method of claim 9245 whereinthe fibrosing agent is or comprises silk. 9256-9259. (canceled) 9260.The method of claim 9245 wherein the fibrosing agent is or comprisesbleomycin. 9261-9314. (canceled)
 9315. The method of claim 9245, whereinthe implant is further combined with a second pharmaceutically activeagent.
 9316. (canceled)
 9317. The method of claim 9245 wherein theimplant is further combined with an agent that inhibits infection.9318-9366. (canceled)
 9367. A method of making a medical devicecomprising combining i) a vaso-occlusion implant, with ii) a fibrosingagent or a composition comprising a fibrosing agent, where the fibrosingagent induces a fibrotic response between the device and a patient inwhich the device is implanted.
 9368. (canceled)
 9369. The method ofclaim 9367 wherein the fibrosing agent promotes angiogenesis.
 9370. Themethod of claim 9367 wherein the fibrosing agent promotes fibroblastmigration.
 9371. The method of claim 9367 wherein the fibrosing agentpromotes fibroblast proliferation.
 9372. The method of claim 9367wherein the fibrosing agent promotes deposition of extracellular matrix(ECM).
 9373. The method of claim 9367 wherein the fibrosing agentpromotes tissue remodeling.
 9374. The method of claim 9367 wherein thefibrosing agent is an arterial vessel wall irritant.
 9375. (canceled)9376. (canceled)
 9377. The method of claim 9367 wherein the fibrosingagent is or comprises silk. 9378-9381. (canceled)
 9382. The method ofclaim 9367 wherein the fibrosing agent is or comprises bleomycin.9383-9436. (canceled)
 9437. The method of claim 9367, wherein theimplant is further combined with a second pharmaceutically active agent.9438. (canceled)
 9439. The method of claim 9367 wherein the implant isfurther combined with an agent that inhibits infection. 9440-9488.(canceled)
 9489. A method of making a medical device comprisingcombining i) a non-coiled vaso-occlusive implant, with ii) a fibrosingagent or a composition comprising a fibrosing agent, where the fibrosingagent induces a fibrotic response between the device and a patient inwhich the device is implanted.
 9490. (canceled)
 9491. The method ofclaim 9489 wherein the fibrosing agent promotes angiogenesis.
 9492. Themethod of claim 9489 wherein the fibrosing agent promotes fibroblastmigration.
 9493. The method of claim 9489 wherein the fibrosing agentpromotes fibroblast proliferation.
 9494. The method of claim 9489wherein the fibrosing agent promotes deposition of extracellular matrix(ECM).
 9495. The method of claim 9489 wherein the fibrosing agentpromotes tissue remodeling.
 9496. The method of claim 9489 wherein thefibrosing agent is an arterial vessel wall irritant.
 9497. (canceled)9498. (canceled)
 9499. The method of claim 9489 wherein the fibrosingagent is or comprises silk. 9500-9503. (canceled)
 9504. The method ofclaim 9489 wherein the fibrosing agent is or comprises bleomycin.9505-9558. (canceled)
 9559. The method of claim 9489, wherein theimplant is further combined with a second pharmaceutically active agent.9560. (canceled)
 9561. The method of claim 9489 wherein the implant isfurther combined with an agent that inhibits infection. 9562-10247.(canceled)